Bicyclic heterocycles as fgfr inhibitors

ABSTRACT

The present invention relates to bicyclic heterocycles, and pharmaceutical compositions of the same, that are inhibitors of the FGFR enzyme and are useful in the treatment of FGFR-associated diseases such as cancer.

PRIORITY CLAIM

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/915,750, filed on Oct. 16, 2019, the entirety of which isincorporated by reference herein.

FIELD OF THE INVENTION

The present disclosure relates to bicyclic heterocycles, andpharmaceutical compositions of the same, that are inhibitors of theenzyme FGFR and are useful in the treatment of FGFR-associated diseasessuch as cancer.

BACKGROUND OF INVENTION

The Fibroblast Growth Factor Receptors (FGFR) are receptor tyrosinekinases that bind to fibroblast growth factor (FGF) ligands. There arefour FGFR proteins (FGFR1-4) that are capable of binding ligands and areinvolved in the regulation of many physiological processes includingtissue development, angiogenesis, wound healing, and metabolicregulation. Upon ligand binding, the receptors undergo dimerization andphosphorylation leading to stimulation of the protein kinase activityand recruitment of many intracellular docking proteins. Theseinteractions facilitate the activation of an array of intracellularsignaling pathways including Ras-MAPK, AKT-PI3K, and phospholipase Cthat are important for cellular growth, proliferation and survival(Reviewed in Eswarakumar et al. Cytokine & Growth Factor Reviews, 2005,16, 139-149). Aberrant activation of this pathway either throughoverexpression of FGF ligands or FGFR or activating mutations in theFGFRs can lead to tumor development, progression, and resistance toconventional cancer therapies. In human cancer, genetic alterationsincluding gene amplification, chromosomal translocations and somaticmutations that lead to ligand-independent receptor activation have beendescribed (Reviewed in Knights and Cook, Pharmacology & Therapeutics,2010, 125, 105-117; Turner and Grose, Nature Reviews Cancer, 2010, 10,116-129). Large scale DNA sequencing of thousands of tumor samples hasrevealed that FGFR genes are altered in many cancers (Helsten et al.Clin Cancer Res. 2016, 22, 259-267). Some of these activating mutationsare identical to germline mutations that lead to skeletal dysplasiasyndromes (Gallo et al. Cytokine & Growth Factor Reviews 2015, 26,425-449). Mechanisms that lead to aberrant ligand-dependent signaling inhuman disease include overexpression of FGFs and changes in FGFRsplicing that lead to receptors with more promiscuous ligand bindingabilities. Therefore, development of inhibitors targeting FGFR may beuseful in the clinical treatment of diseases that have elevated FGF orFGFR activity.

The cancer types in which FGF/FGFRs are implicated include, but are notlimited to: carcinomas (e.g., bladder, breast, colorectal, endometrial,gastric, head and neck, kidney, lung, ovarian, prostate); hematopoieticmalignancies (e.g., multiple myeloma, acute myelogenous leukemia, andmyeloproliferative neoplasms); and other neoplasms (e.g., glioblastomaand sarcomas). In addition to a role in oncogenic neoplasms, FGFRactivation has also been implicated in skeletal and chondrocytedisorders including, but not limited to, achrondroplasia andcraniosynostosis syndromes.

There is a continuing need for the development of new drugs for thetreatment of cancer, and the FGFR inhibitors described herein helpaddress this need.

SUMMARY OF INVENTION

The present disclosure is directed to compounds having Formula (I):

or pharmaceutically acceptable salts thereof, wherein constituentvariables are defined herein.

The present disclosure is further directed to pharmaceuticalcompositions comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.

The present disclosure is further directed to methods of inhibiting anFGFR enzyme (e.g., an FGFR3 enzyme) comprising contacting the enzymewith a compound of Formula (I), or a pharmaceutically acceptable saltthereof.

The present disclosure is further directed to a method of treating adisease associated with abnormal activity or expression of an FGFRenzyme (e.g., an FGFR3 enzyme), comprising administering a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, to a patientin need thereof.

The present disclosure is further directed to compounds of Formula (I)for use in treating a disease associated with abnormal activity orexpression of an FGFR enzyme (e.g., an FGFR3 enzyme).

The present disclosure is further directed to a method for treating adisorder mediated by an FGFR enzyme (e.g., an FGFR3 enzyme), or a mutantthereof, in a patient in need thereof, comprising the step ofadministering to said patient a compound of Formula (I), orpharmaceutically acceptable composition thereof.

The present disclosure is further directed to a method for treating adisorder mediated by an FGFR enzyme (e.g., an FGFR3 enzyme), or a mutantthereof, in a patient in need thereof, comprising the step ofadministering to the patient a compound of Formula (I), or apharmaceutically acceptable salt thereof, or a composition comprising acompound of Formula (I), or a pharmaceutically acceptable salt thereof,in combination with another therapy or therapeutic agent as describedherein.

The present disclosure is further directed to the use of compounds ofFormula (I) in the preparation of a medicament for use in therapy.

DETAILED DESCRIPTION Compounds

In one aspect, the present disclosure provides compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Cy¹ is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; whereinthe 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3 or 4 substituents independently selected from R¹⁰;

R¹ is OR³ or NR⁴R⁵;

R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, halo, CN, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²⁰;

A¹ is N or CR⁶;

A² is N or CR⁷;

A³ is N or CR⁸;

A⁴ is N or CR⁹;

R³ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-14 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and 5-10membered heteroaryl-C₁₋₃ alkylene; wherein said C₁₋₆ alkyl issubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(30A); and wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-14 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-14 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³⁰;

R⁴ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-14 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and 5-10membered heteroaryl-C₁₋₃ alkylene; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-14 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-14 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁴⁰;

R⁵ is selected from H and C₁₋₆ alkyl; wherein said C₁₋₆ alkyl isoptionally substituted with 1 or 2 substituents independently selectedfrom R^(g);

R⁶, R⁷, R⁸, and R⁹ are each independently selected from H, D, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,CN, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR²R², C(O)OR^(a2), NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),C(═NR^(e1))R^(b1), C(═NOR^(a1))R^(b1), C(═NR^(c1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3) NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3) S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a4),SR^(a4), C(O)R^(b4), C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4)NR⁴C(O)OR^(a4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g);

each R^(30A) is independently selected from C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6) NR⁶C(O)R^(b6),NR⁶C(O)OR^(a6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR⁶S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), andS(O)₂NR^(c6)R^(d6); wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R³¹;

each R³⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,OR^(a6), SR^(a6), C(O)R^(b), C(O)NR^(c6)R^(d6), C(O)OR^(a6),NR^(c6)R^(d6), NR⁶C(O)R^(b6)NR^(c6)C(O)OR^(a6), NR⁶S(O)R^(b6),NR⁶S(O)₂R^(b6), NR⁶S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R³¹;

each R³¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a8),SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8), NR^(c8)S(O)R^(b8),NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)₂R^(b8), and S(O)₂NR^(c8)R^(d8); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R⁴⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN,OR^(a7), SR⁷, C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7),NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁴¹;

each R⁴¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a9),SR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9), NR^(c9)R^(d9)NR⁹C(O)R^(b9), NR^(c9)C(O)OR^(a9) NR⁹S(O)R^(b9), NR⁹S(O)₂R⁹,NR⁹S(O)₂NR^(c9)R^(d9), S(O)R^(b9), S(O)NR^(c9)R^(d9), S(O)₂R, andS(O)₂NR^(c9)R^(d9); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²⁰;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²⁰;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²⁰;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R^(a4), R^(c) and R^(d4) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R^(g);

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g);

each R^(a5), R^(c5) and R^(d5) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

or any R^(c5) and R^(d5) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a6), R^(c6) and R^(d6) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³¹;

or any R^(c6) and R^(d6) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R³¹;

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR³¹;

each R^(a7), R^(c7) and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴¹;

or any R^(c7) and R^(d7) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R⁴¹;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁴¹;

each R^(a8), R^(c8) and R^(d8) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b8) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a9), R^(c9) and R^(d9) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b9) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments, A¹ is CR⁶. In some embodiments, A¹ is N.

In some embodiments, A² is CR⁷. In some embodiments, A² is N.

In some embodiments, A³ is CR⁸. In some embodiments, A³ is N.

In some embodiments, A⁴ is CR⁹. In some embodiments, A⁴ is N.

In some embodiments, A¹ is CR⁶; A² is CR⁷; A³ is CR; and A⁴ is CR⁹.

In some embodiments, A¹ is CR⁶; A² is CR⁷; and A⁴ is CR⁹.

In some embodiments, A¹ is CR⁶; A² is CR⁷; A³ is N; and A⁴ is CR⁹.

In some embodiments, A², A³, and A⁴ are each CH.

In some embodiments, A² and A³ are each CH.

In some embodiments, A² is CH.

In some embodiments, A² and A⁴ are each CH.

In some embodiments, R⁶, R⁷, R⁸, and R⁹ are each independently selectedfrom H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R²⁰.

In some embodiments, R⁶, R⁷, R⁸, and R⁹ are each independently selectedfrom H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-10 membered heteroaryl, halo,CN, OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2)S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²⁰

In some embodiments, R⁶, R⁷, R⁸, and R⁹ are each independently selectedfrom H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl is optionally substitutedwith 1 or 2 substituents independently selected from R²⁰.

In some embodiments, R⁶, R⁷, R⁸, and R⁹ are each independently selectedfrom H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, R⁶, R⁷, R⁸, and R⁹ are each independently selectedfrom H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2),C(O)NR^(c2)R^(d2), NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, R⁶, R⁷, R⁸, and R⁹ are each independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2),C(O)NR^(c2)R^(d2), and S(O)₂R^(b2).

In some embodiments, R⁶, R⁷, R⁸, and R⁹ are each independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-10 membered heteroaryl, halo, CN,OR^(a), C(O)NR^(c2)R^(d2), and S(O)₂R^(b2).

In some embodiments, R⁶ is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), NR^(c2)R^(d2) S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2).

In some embodiments, R⁶ is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a2), C(O)NR^(c2)R^(d2), NR^(c2)R^(d2),S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, R⁶ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a2), C(O)NR^(c2)R^(d2), and S(O)₂R^(b2).

In some embodiments, R⁶ is H or C(O)NR^(c2)R^(d2). In some embodiments,R⁶ is H. In some embodiments, R⁶ is C(O)NR^(c2)R^(d2). In someembodiments, R⁶ is H or C(O)NHCH₃. In some embodiments, R⁶ is C(O)NHCH₃.In some embodiments, R⁶ is H or 5-10 membered heteroaryl.

In some embodiments, R⁷ is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), NR^(c2)R^(d2) S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2).

In some embodiments, R⁷ is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a2), C(O)NR^(c2)R^(d2), NR^(c2)R^(d2),S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, R⁷ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a2), C(O)NR^(c2)R^(d2), and S(O)₂R^(b2). In someembodiments, R⁷ is H.

In some embodiments, R⁸ is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR²R²,C(O)OR^(a2), NR^(c2)R^(d2) S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2).

In some embodiments, R⁸ is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a2), C(O)NR^(c2)R^(d2),NR^(c2)R^(d2)S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, R⁸ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a2), C(O)NR^(c2)R^(d2), and S(O)₂R^(b2).

In some embodiments, R⁸ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN,OR^(a2), or S(O)₂R^(b2). In some embodiments, R⁸ is H, methyl, CHF₂, F,CN, OH, or S(O)₂(CH₃)₂. In some embodiments, R⁸ is C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a2), or S(O)₂R^(b2). In some embodiments, R⁸ isH.

In some embodiments, R⁹ is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2).

In some embodiments, R⁹ is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a2), C(O)NR^(c2)R^(d2),NR^(c2)R^(d2)S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2). In some embodiments,R⁹ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2).C(O)NR^(c2)R^(d2), and S(O)₂R^(b2).

In some embodiments, R⁹ is H or halo. In some embodiments, R⁹ is H. Insome embodiments, R⁹ is halo. In some embodiments, R⁹ is H or F. In someembodiments, R⁹ is F.

In some embodiments, R¹ is OR³.

In some embodiments, R¹ is NR⁴R⁵.

In some embodiments, R³ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl is substituted with 1, 2,3, or 4 substituents independently selected from R^(30A) and whereinsaid 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R³⁰.

In some embodiments, R³ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 memberedheteroaryl; wherein said C₁₋₆ alkyl is substituted with 1, 2, 3, or 4substituents independently selected from R^(30A) and wherein said 4-6membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R³⁰.

In some embodiments, R³ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, and4-6 membered heterocycloalkyl; wherein said C₁₋₆ alkyl is substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(30A) andwherein said 4-6 membered heterocycloalkyl is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R³⁰.

In some embodiments, R³ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, and4-6 membered heterocycloalkyl; wherein said C₁₋₆ alkyl is substitutedwith 1 or 2 substituents independently selected from R^(30A) and whereinsaid 4-6 membered heterocycloalkyl is optionally substituted with 1 or 2substituents independently selected from R³⁰.

In some embodiments, R³ is selected from 4-14 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl; each of which is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR³⁰.

In some embodiments, R³ is 4-14 membered heterocycloalkyl optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR³⁰. In some embodiments, R³ is 4-6 membered heterocycloalkyl optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR³⁰. In some embodiments, R³ is 4-6 membered heterocycloalkyl optionallysubstituted with 1 or 2 substituents independently selected from R³⁰.

In some embodiments, R³ is tetrahydrofuranyl optionally substituted with1, 2, 3, or 4 substituents independently selected from R³⁰. In someembodiments, R³ is tetrahydrofuran-3-yl optionally substituted with 1,2, 3, or 4 substituents independently selected from R³⁰. In someembodiments, R³ is tetrahydrofuran-3-yl optionally substituted with 1 or2 substituents independently selected from R³⁰.

In some embodiments, R³ is 4-14 membered heterocycloalkyl. In someembodiments, R³ is 4-6 membered heterocycloalkyl. In some embodiments,R³ is 5-6 membered heterocycloalkyl.

In some embodiments, R³ is 5 membered heterocycloalkyl. In someembodiments, R³ is tetrahydrofuranyl.

In some embodiments, R³ is tetrahydrofuran-3-yl.

In some embodiments, R⁴ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-14membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰.

In some embodiments, R⁴ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6membered heteroaryl; wherein said C₁₋₆ alkyl, C₃. 6 cycloalkyl, 4-6membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴.

In some embodiments, R⁴ is 4-14 membered heterocycloalkyl optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁴⁰. In some embodiments, R⁴ is 5-6 membered heterocycloalkyl optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁴⁰. In some embodiments, R⁴ is tetrahydrofuranyl optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R⁴⁰. In someembodiments, R⁴ is tetrahydrofuran-3-yl optionally substituted with 1,2, 3, or 4 substituents independently selected from R⁴⁰.

In some embodiments, R⁴ is 4-14 membered heterocycloalkyl. In someembodiments, R⁴ is 4-6 membered heterocycloalkyl optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R⁴⁰. In someembodiments, R⁴ is 5-6 membered heterocycloalkyl. In some embodiments,R⁴ is 4-6 membered heterocycloalkyl. In some embodiments, R⁴ istetrahydrofuranyl.

In some embodiments, R⁴ is tetrahydrofuran-3-yl.

In some embodiments, R⁵ is selected from H and C₁₋₆ alkyl. In someembodiments, R⁵ is H.

In some embodiments, R² is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, halo, CN, OR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R²⁰.

In some embodiments, R² is selected from H, D, and halo.

In some embodiments, R² is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, halo, CN, OR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2).

In some embodiments, R² is selected from H, D, C₁₋₆ alkyl, and halo.

In some embodiments, R² is H.

In some embodiments, Cy¹ is selected from phenyl and 5-6 memberedheteroaryl; wherein the 5-6 membered heteroaryl has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-6 memberedheteroaryl is optionally substituted by oxo to form a carbonyl group;and wherein the phenyl and 5-6 membered heteroaryl are each optionallysubstituted with 1 or 2 substituents independently selected from R¹⁰.

In some embodiments, Cy¹ is selected from phenyl and 5-6 memberedheteroaryl; wherein the phenyl and 5-6 membered heteroaryl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰. In some embodiments, Cy¹ is selected from phenyl and5-6 membered heteroaryl; wherein the phenyl and 5-6 membered heteroarylare each optionally substituted with 1 or 2 substituents independentlyselected from R¹⁰. In some embodiments, Cy¹ is selected from phenyl and5-6 membered heteroaryl; wherein the phenyl and 5-6 membered heteroarylare each substituted with 1 or 2 substituents independently selectedfrom R¹⁰. In some embodiments, Cy¹ is selected from phenyl and 5-6membered heteroaryl; wherein the phenyl and 5-6 membered heteroaryl areeach substituted with 1 substituent 15 independently selected from R¹⁰.

In some embodiments, Cy¹ is phenyl, pyrazolyl or pyridinyl, each ofwhich is optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹⁰. In some embodiments, Cy¹ is phenyl,pyrazolyl or pyridinyl, each of which is optionally substituted with 1or 2 substituents independently selected from R¹⁰. In some embodiments,wherein Cy¹ is phenyl, pyrazolyl, triazolyl, oxazolyl,2-oxo-1,2-dihydropyridinyl, pyridazinyl, or pyridinyl, each of which isoptionally substituted with 1 or 2 substituents independently selectedfrom R¹⁰. In some embodiments, Cy¹ is phenyl, pyrazolyl or pyridinyl,each of which is substituted with 1 or 2 substituents independentlyselected from R¹⁰. In some embodiments, Cy¹ is phenyl, pyrazolyl orpyridinyl, each of which is optionally substituted with 1 substituentindependently selected from R¹⁰.

In some embodiments, Cy¹ is 5-10 membered heteroaryl optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹⁰. In some embodiments, Cy¹ is 5-10 membered heteroaryl optionallysubstituted with 1 or 2 substituents independently selected from R¹⁰. Insome embodiments, Cy¹ is 5-10 membered heteroaryl optionally substitutedwith 1 substituent independently selected from R¹⁰. In some embodiments,Cy¹ is 5-10 membered heteroaryl substituted with 1 or 2 substituentsindependently selected from R¹⁰.

In some embodiments, Cy¹ is 5-6 membered heteroaryl optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹⁰. In some embodiments, Cy¹ is 5-6 membered heteroaryl optionallysubstituted with 1 or 2 substituents independently selected from R¹⁰. Insome embodiments, Cy¹ is 5-6 membered heteroaryl optionally substitutedwith 1 substituent independently selected from R¹⁰. In some embodiments,Cy¹ is 5-6 membered heteroaryl substituted with 1 or 2 substituentsindependently selected from R¹⁰.

In some embodiments, Cy¹ is pyrazolyl or pyridinyl, each of which isoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰. In some embodiments, Cy¹ is pyrazolyl or pyridinyl,each of which is optionally substituted with 1 or 2 substituentsindependently selected from R¹⁰. In some embodiments, Cy¹ is pyrazolylor pyridinyl, each of which is substituted with 1 or 2 substituentsindependently selected from R¹⁰. In some embodiments, Cy¹ is pyrazolylor pyridinyl, each of which is optionally substituted with 1 substituentindependently selected from R¹⁰.

In some embodiments, Cy¹ is pyrazol-4-yl, pyridin-3-yl, or pyridin-4-yl,each of which is optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹⁰. In some embodiments, Cy¹ ispyrazol-4-yl, pyridin-3-yl, or pyridin-4-yl, each optionally substitutedwith 1 or 2 substituents independently selected from R¹⁰. In someembodiments, Cy¹ is pyrazol-4-yl, pyridin-3-yl, or pyridin-4-yl, eachoptionally substituted with 1 substituent independently selected fromR¹⁰.

In some embodiments, Cy¹ is pyrazolyl optionally substituted with 1, 2,3 or 4 substituents independently selected from R¹⁰. In someembodiments, Cy¹ is pyrazolyl optionally substituted with 1 or 2substituents independently selected from R¹⁰. In some embodiments, Cy¹is pyrazolyl optionally substituted with 1 substituent independentlyselected from R¹⁰.

In some embodiments, Cy¹ is pyridinyl optionally substituted with 1, 2,3 or 4 substituents independently selected from R¹⁰. In someembodiments, Cy¹ is pyridinyl optionally substituted with 1 or 2substituents independently selected from R¹⁰. In some embodiments, Cy¹is pyridinyl optionally substituted with 1 substituent independentlyselected from R¹⁰.

In some embodiments, Cy¹ is C₆₋₁₀ aryl optionally substituted with 1, 2,3 or 4 substituents independently selected from R¹⁰. In someembodiments, Cy¹ is C₆₋₁₀ aryl optionally substituted with 1 or 2substituents independently selected from R¹⁰. In some embodiments, Cy¹is C₆₋₁₀ aryl substituted with 1 or 2 substituents independentlyselected from R¹⁰. In some embodiments, Cy¹ is C₆₋₁₀ aryl substitutedwith 1 substituent independently selected from R¹⁰.

In some embodiments, Cy¹ is phenyl optionally substituted with 1, 2, 3or 4 substituents independently selected from R¹⁰. In some embodiments,Cy¹ is phenyl optionally substituted with 1 or 2 substituentsindependently selected from R¹⁰. In some embodiments, Cy¹ is phenylsubstituted with 1 or 2 substituents independently selected from R¹⁰. Insome embodiments, Cy¹ is phenyl substituted with 1 substituentindependently selected from R¹⁰.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halo, D, CN, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); whereinsaid C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halo, D, CN, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); whereinsaid C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl are each optionally substituted with1 or 2 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halo, D, CN, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); whereinsaid C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl are each optionally substituted with1 substituent independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, and NR^(c1)R^(d1);wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, and NR^(c1)R^(d1);wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted with 1 or 2substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, halo, D,CN, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); wherein saidC₁₋₆ alkyl, C₃₋₆ cycloalkyl, and 4-6 membered heterocycloalkyl are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, halo, D,CN, OR^(a1), and NR^(c1)R^(d1); wherein said C₁₋₆ alkyl and 4-6 memberedheterocycloalkyl are each optionally substituted with 1 or 2substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and NR^(c1)R^(d1);wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and 4-6 memberedheterocycloalkyl are each optionally substituted with 1 or 2substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from methyl,ethyl, propyl, isopropyl, piperidinyl, piperazinyl, azetidinyl,morpholino, cyclopropyl, and cyclobutyl; each of which is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹. In some embodiments, each R¹⁰ is independently selected frommethyl, ethyl, propyl, isopropyl, piperidinyl, piperazinyl, azetidinyl,morpholino, cyclopropyl, and cyclobutyl; each of which is optionallysubstituted with 1 or 2 substituents independently selected from R¹¹. Insome embodiments, each R¹⁰ is independently selected from methyl, ethyl,propyl, isopropyl, piperidinyl, piperazinyl, azetidinyl, morpholino,cyclopropyl, ethylamino, and cyclobutyl; each of which is optionallysubstituted with 1 or 2 substituents independently selected from R¹¹. Insome embodiments, each R¹⁰ is independently selected from methyl, ethyl,propyl, isopropyl, piperidinyl, piperazinyl, azetidinyl, morpholino,cyclopropyl, and cyclobutyl; each of which is optionally substitutedwith 1 substituent independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from methyl,isopropyl, 2-hydroxypropan-2-yl, NH(CH₃), methylpiperidin-4-yl,methylpiperazin-1-yl, morpholinoethyl, 1-methylazetidin-3-yl,morpholino, cyclopropyl, and cyclobutyl.

In some embodiments, each R¹⁰ is independently selected from methyl,ethyl, isopropyl, 2-hydroxypropan-2-yl, NH(CH₃), methylpiperidin-4-yl,methylpiperazin-1-yl, morpholinoethyl, 1-methylazetidin-3-yl,morpholino, cyclopropyl, ethylamino, hydroxyethyl-2-yl, cyanoethyl-2-yl,dimethylamino-2-oxoethyl, 2-hydroxy-2-methylpropyl, 2-methoxyethyl,pyridin-3-ylmethyl, (tetrahydro-2H-pyran-4-yl)methyl, 2-morpholinoethyl,3-fluoro-1-methylpiperidin-4-yl,((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl,1-isopropylpiperidin-4-yl, 4-fluoro-1-methylpiperidin-4-yl,4-methylpiperazin-1-yl, tetrahydrofuran-3-yl,1,1-dioxidotetrahydrothiophen-3-yl, and cyclobutyl.

In some embodiments, each R¹⁰ is C₁₋₆ alkyl. In some embodiments, R¹⁰ ismethyl.

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), NR³C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)S(O)₂R^(b3) NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, 20 C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, halo,D, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3) and S(O)₂R³.

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, halo, D,CN, OR^(a3), and NR^(c3)R^(d3).

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3) NR^(c3)C(O)R^(b3)NR^(c3)C(O)OR^(a3), (check hold up with missing letter at beginning)NR^(c3)S(O)₂R³, NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)₂R^(b3), andS(O)₂NR^(c3)R^(d3).

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,4-10 membered heterocycloalkyl, and OR^(a3); wherein said C₁₋₆ alkyl,and 4-10 membered heterocycloalkyl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹². In someembodiments, each R¹¹ is independently selected from C₁₋₆ alkyl, 4-10membered heterocycloalkyl, and OR^(a3).

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,4-6 membered heterocycloalkyl, and OR^(a3); wherein said C₁₋₆ alkyl and4-6 membered heterocycloalkyl are each optionally substituted with 1 or2 substituents independently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,CN, 4-7 membered heterocycloalkyl, C(O)NR^(c3)R^(d3), halo, 5-10membered heteroaryl, and OR^(a3); wherein said C₁₋₆ alkyl and 4-7membered heterocycloalkyl are each optionally substituted with 1 or 2substituents independently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,4-6 membered heterocycloalkyl, and OR^(a3). In some embodiments, eachR¹¹ is independently selected from C₁₋₆ alkyl, CN, 4-7 memberedheterocycloalkyl, C(O)NR^(c3)R^(d3), halo, and OR^(a3). In someembodiments, each R¹¹ is independently selected from C₁₋₆ alkyl, 5-6membered heterocycloalkyl, and OR^(a3). In some embodiments, each R¹¹ isindependently selected from C₁₋₆ alkyl, 6 membered heterocycloalkyl, andOR^(a3).

In some embodiments, each R¹¹ is independently selected from methyl, OH,and morpholino.

In some embodiments, each R¹¹ is independently selected from methyl, OH,methoxy, CN, C(O)N(CH₃)₂, isopropyl, pyridinyl, tetrahydropyranyl,fluoro, 2-oxa-5-azabicyclo[2.2.1]heptanyl, and morpholino.

In some embodiments, each R¹¹ is C₁₋₆ alkyl. In some embodiments, eachR¹¹ is methyl.

In some embodiments, each R¹¹ is C₁₋₆ alkyl or OR^(a3). In someembodiments, each R¹¹ is methyl or OH.

In some embodiments, each R¹² is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5) NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g).

In some embodiments, each R¹² is independently selected from C₁₋₆ alkyland halo. In some embodiments, each R¹² is independently selected fromC₁₋₆ alkyl.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN, OR^(a4), SR^(a4), C(O)R^(b4), C(O)OR^(a4),NR^(c4)R^(d4) NR⁴C(O)R^(b4) NR⁴S(O)₂R^(b4), S(O)₂R^(b4), andS(O)₂NR^(c4)R^(d4); wherein said C₁₋₆ alkyl is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g).

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyland halo. In some embodiments, each R²⁰ is independently selected fromC₁₋₆ alkyl.

In some embodiments, each R²⁰ is independently selected from halo, D,CN, OR^(a4), and NR^(c4)R^(d4) In some embodiments, each R²⁰ isindependently selected from D.

In some embodiments, each R^(30A) is independently selected from C₁₋₆haloalkyl, halo, D, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), NR^(c6)R^(d6), NR⁶C(O)R^(b6), NR⁶S(O)R^(b6),NR^(c6)S(O)₂R^(b6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6).

In some embodiments, each R^(3A) is independently selected from halo,CN, OR^(a6), and NR⁶R^(d6).

In some embodiments, each R^(3A) is independently selected from halo.

In some embodiments, each R³⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl halo, D, CN, OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), and NR^(c6)R^(d6).

In some embodiments, each R³¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN, OR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8),C(O)OR^(a8), NR^(c8)R^(d8) and S(O)₂R^(b8); wherein said C₁₋₆ alkyl, isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g).

In some embodiments, each R³¹ is independently selected from C₁₋₆ alkyland halo. In some embodiments, each R³¹ is independently selected fromC₁₋₆ alkyl.

In some embodiments, each R⁴⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7) NR^(c7)C(O)R^(b7),NR^(c7)S(O)₂R^(b7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7); wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴¹.

In some embodiments, each R⁴⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN, OR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7),C(O)OR^(a7), and NR^(c7)R^(d7).

In some embodiments, each R⁴⁰ is independently selected from C₁₋₆ alkyland halo. In some embodiments, each R⁴⁰ is independently selected fromC₁₋₆ alkyl.

In some embodiments, each R⁴¹ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, D, CN, OR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9),C(O)OR^(a9), NR^(c9)R^(d9) and S(O)₂R^(b9); wherein said C₁₋₆ alkyl isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g).

In some embodiments, each R⁴¹ is independently selected from C₁₋₆ alkyland halo. In some embodiments, each R⁴¹ is independently selected fromC₁₋₆ alkyl.

In some embodiments, each R^(a1), R^(c1) and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl; or any R^(c1) and R^(d1) attached to the sameN atom, together with the N atom to which they are attached, form a 4-,5-, or 6-membered heterocycloalkyl group optionally substituted with 1,2, 3, or 4 substituents independently selected from R¹¹.

In some embodiments, each R^(a1), R^(c1) and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, each R^(a1), R^(c1) and R^(d1) is independentlyselected from H and C₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹. In some embodiments, each R^(a1), R^(c1) and R^(d1) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(b1) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl.

In some embodiments, each R^(b1) is independently selected from C₁₋₆alkyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹. In some embodiments, each R^(b1) isindependently selected from C₁₋₆ alkyl.

In some embodiments, each R^(a2), R^(c2), and R^(d2) is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, each R^(a2), R^(c2) and R^(d2) is independentlyselected from H and C₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²⁰. In some embodiments, each R^(a2), R^(c2) and R^(d2) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(c2) and R^(d2) is independently selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, each R^(b2) is independently selected from C₁₋₆alkyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²⁰. In some embodiments, each R^(b2) isindependently selected from C₁₋₆ alkyl.

In some embodiments, each R^(b2) is independently selected from C₁₋₆alkyl and C₁₋₆ haloalkyl.

In some embodiments, each R^(a3), R^(c3) and R^(d3), is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, each R^(a3), R^(c3) and R^(d3) is independentlyselected from H and C₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹². In some embodiments, each R^(a3), R^(c3) and R^(d3) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(b3) is independently selected from C₁₋₆alkyl and C₁₋₆ haloalkyl.

In some embodiments, each R^(b3) is independently selected from C₁₋₆alkyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹². In some embodiments, each R^(b3) isindependently selected from C₁₋₆ alkyl.

In some embodiments, each R^(a4), R^(c4) and R^(d4), is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, each R^(a5), R^(c5) and R^(d5) is independentlyselected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a6), R^(c6) and R^(d6) is independentlyselected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a6), R^(c6) and R^(d6), is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, each R^(b6) is independently selected from C₁₋₆alkyl.

In some embodiments, each R^(b6) is independently selected from C₁₋₆alkyl and C₁₋₆ haloalkyl.

In some embodiments, each R^(a7), R^(c7) and R^(d7) is independentlyselected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a7), R^(c7) and R^(d7), is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, each R^(b7) is independently selected from C₁₋₆alkyl.

In some embodiments, each R^(b7) is independently selected from C₁₋₆alkyl and C₁₋₆ haloalkyl.

In some embodiments the compound of Formula I is a compound of FormulaIIa:

or a pharmaceutically acceptable salt thereof, wherein Cy¹, R¹, R⁶, R⁸,and R⁹ are as defined herein.

In some embodiments the compound of Formula I is a compound of FormulaIIb:

or a pharmaceutically acceptable salt thereof, wherein Cy¹, R¹, and R⁶are as defined herein.

In some embodiments the compound of Formula I is a compound of FormulaIIIa:

or a pharmaceutically acceptable salt thereof, wherein X is O or NH; andwherein Cy¹, R², A¹, A², A³, and A⁴ are as defined herein. In someembodiments, X is O. In some embodiments, X is NH.

In some embodiments the compound of Formula I is a compound of FormulaIIIb:

or a pharmaceutically acceptable salt thereof, wherein X is O or NH; andwherein Cy¹, R⁶, R⁹, and A³ are as defined herein. In some embodiments,X is O. In some embodiments, X is NH.

In some embodiments the compound of Formula I is a compound of FormulaIVa:

or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3,or 4, and wherein R³, R⁶, R⁹, R¹⁰, and A³ are as defined herein. In someembodiments, n is 0, 1, 2 or 3. In some embodiments, n is 0, 1, or 2. Insome embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In someembodiments, n is 0. In some embodiments, n is 1. In some embodiments, nis 2.

In some embodiments the compound of Formula I is a compound of FormulaIVb:

or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3,or 4, and wherein R³, R⁶, R⁹, R¹⁰, and A³ are as defined herein. In someembodiments, n is 0, 1, 2 or 3. In some embodiments, n is 0, 1, or 2. Insome embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In someembodiments, n is 0. In some embodiments, n is 1. In some embodiments, nis 2.

In some embodiments the compound of Formula I is a compound of FormulaIVc:

or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or3, and wherein R³, R⁶, R⁹, R¹⁰, and A³ are as defined herein. In someembodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In someembodiments, n is 1.

In some embodiments the compound of Formula I is a compound of FormulaV:

or a pharmaceutically acceptable salt thereof, wherein X is O or NH; andwherein R⁶, R⁹, R¹⁰, and A³ are as defined herein. In some embodiments,X is O. In some embodiments, X is NH.

In some embodiments, provided herein is a compound of Formula (I),wherein:

Cy¹ is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; whereinthe 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3 or 4 substituents independently selected from R¹⁰;

R¹ is OR³ or NR⁴R⁵;

R² is selected from H, D, and halo;

A¹ is selected from N and CR⁶;

A² is selected from N and CR⁷;

A³ is selected from N and CR⁸;

A⁴ is selected from N and CR⁹;

R³ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-14membered heterocycloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-14 memberedheterocycloalkyl-C₁₋₃ alkylene, and C₆₋₁₀ aryl-C₁₋₃ alkylene; whereinsaid C₁₋₆ alkyl is substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(30A) and wherein said C₃₋₁₀ cycloalkyl,4-14 membered heterocycloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-14membered heterocycloalkyl-C₁₋₃ alkylene, and C₆₋₁₀ aryl-C₁₋₃ alkyleneare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³⁰;

R⁴ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-14membered heterocycloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-14 memberedheterocycloalkyl-C₁₋₃ alkylene, and C₆₋₁₀ aryl-C₁₋₃ alkylene; whereinsaid C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-14 membered heterocycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-14 membered heterocycloalkyl-C₁₋₃ alkylene,and C₆₋₁₀ aryl-C₁₋₃ alkylene are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R⁴⁰;

R⁵ is H;

R⁶, R⁷, R⁸, and R⁹ are each independently selected from H, D, C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); whereinsaid C₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4substituents independently selected from R²⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); wherein saidC₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR^(a3),C(O)R^(b3), C(O)N^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), andS(O)₂R^(b3);

each R²⁰ is independently selected from halo, D, CN, OR^(a4), andNR^(c4)R^(d4);

each R^(30A) is independently selected from halo, CN, OR^(a6), andNR^(c6)R^(d6);

each R³⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl halo,D, CN, OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), andNR^(c6)R^(d6);

each R⁴⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), andNR^(c7)R^(d7);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; each R^(b2) is independently selected fromC₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; each R^(b3) is independently selected fromC₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

each R^(a6), R^(c6) and R^(d6), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

each R^(b6) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl;

each R^(a7), R^(c7) and R^(d7), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; and

each R^(b7) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments, provided herein is a compound of Formula (I),wherein:

Cy¹ is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; whereinthe 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3 or 4 substituents independently selected from R¹⁰;

R¹ is OR³ or NR⁴R⁵;

R² is selected from H, D, and halo;

A¹ is CR⁶;

A² is CR⁷;

A³ is CR or N;

A⁴ is CR⁹;

R³ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-14membered heterocycloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-14 memberedheterocycloalkyl-C₁₋₃ alkylene, and C₆₋₁₀ aryl-C₁₋₃ alkylene; whereinsaid C₁₋₆ alkyl is substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(30A) and wherein said C₃₋₁₀ cycloalkyl,4-14 membered heterocycloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-14membered heterocycloalkyl-C₁₋₃ alkylene, and C₆₋₁₀ aryl-C₁₋₃ alkyleneare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³⁰;

R⁴ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-14membered heterocycloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-14 memberedheterocycloalkyl-C₁₋₃ alkylene, and C₆₋₁₀ aryl-C₁₋₃ alkylene; whereinsaid C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-14 membered heterocycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-14 membered heterocycloalkyl-C₁₋₃ alkylene,and C₆₋₁₀ aryl-C₁₋₃ alkylene are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R⁴⁰;

R⁵ is H;

R⁶, R⁷, R⁸, and R⁹ are each independently selected from H, D, C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); whereinsaid C₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4substituents independently selected from R²⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); wherein saidC₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR^(a3),C(O)R^(b3), C(O)N^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3) andS(O)₂R^(b3);

each R²⁰ is independently selected from halo, D, CN, OR^(a4), andNR^(c4)R^(d4);

each R^(30A) is independently selected from halo, CN, OR^(a6), andNR^(c6)R^(d6);

each R³⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl halo,D, CN, OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), andNR^(c6)R^(d6);

each R⁴⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), andNR^(c7)R^(d7);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

each R^(b2) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

each R^(b3) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl;

each R^(a4), R^(c4) and R^(d4) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

each R^(a6), R^(c6) and R^(d6) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

each R^(b6) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl;

each R^(a7), R^(c7) and R^(d7) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; and

each R^(b7) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments, provided herein is a compound of Formula (I),wherein:

Cy¹ is selected from phenyl and 5-6 membered heteroaryl; wherein the 5-6membered heteroaryl has at least one ring-forming carbon atom and 1, 2,3, or 4 ring-forming heteroatoms independently selected from N, O, andS; wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of 5-6 membered heteroaryl is optionally substituted by oxoto form a carbonyl group; and wherein the phenyl and 5-6 memberedheteroaryl are each optionally substituted with 1 or 2 substituentsindependently selected from R¹⁰;

R¹ is OR³ or NR⁴R⁵;

R² is selected from H, D, and halo;

A¹ is selected from N and CR⁶;

A² is selected from N and CR⁷;

A³ is selected from N and CR⁸;

A⁴ is selected from N and CR⁹;

R³ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6membered heterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₃ alkylene, 4-6 memberedheterocycloalkyl-C₁₋₃ alkylene, and C₆₋₁₀ aryl-C₁₋₃ alkylene; whereinsaid C₁₋₆ alkyl is substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(30A) and wherein said C₃₋₆ cycloalkyl,4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₃ alkylene, 4-6membered heterocycloalkyl-C₁₋₃ alkylene, and C₆₋₁₀ aryl-C₁₋₃ alkyleneare each optionally substituted with 1 or 2 substituents independentlyselected from R³⁰;

R⁴ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6membered heterocycloalkyl, C₃₋₆ cycloalkyl-C₁₋₃ alkylene, 4-6 memberedheterocycloalkyl-C₁₋₃ alkylene, and C₆₋₁₀ aryl-C₁₋₃ alkylene; whereinsaid C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, C₃₋₆cycloalkyl-C₁₋₃ alkylene, 4-6 membered heterocycloalkyl-C₁₋₃ alkylene,and C₆₋₁₀ aryl-C₁₋₃ alkylene are each optionally substituted with 1 or 2substituents independently selected from R⁴⁰;

R⁵ is H;

R⁶, R⁷, R⁸, and R⁹ are each independently selected from H, D, C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); whereinsaid C₁₋₆ alkyl is optionally substituted with 1 or 2 substituentsindependently selected from R²⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); wherein saidC₁₋₆ alkyl, C₃₋₆ cycloalkyl, and 4-6 membered heterocycloalkyl are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR^(a3),C(O)R^(b3), C(O)N^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), andS(O)₂R^(b3);

each R²⁰ is independently selected from halo, D, CN, OR^(a4), andNR^(c4)R^(d4);

each R^(30A) is independently selected from halo, CN, OR^(a6), andNR^(c6)R^(d6);

each R³⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl halo,D, CN, OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), andNR^(c6)R^(d6);

each R⁴⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), andNR^(c7)R^(d7);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; each R^(b2) is independently selected fromC₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; each R^(b3) is independently selected fromC₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(a4), R^(c4) and R^(d4) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

each R^(a6), R^(c6) and R^(d6) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

each R^(b6) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl;

each R^(a7), R^(c7) and R^(d7) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; and

each R^(b7) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments, provided herein is a compound of Formula (I),wherein:

Cy¹ is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; whereinthe 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; and wherein the C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1 or 2 substituents independentlyselected from R¹⁰;

R¹ is OR³ or NR⁴R⁵;

R² is H;

A¹ is selected from N and CR⁶;

A² is selected from N and CR⁷;

A³ is selected from N and CR;

A⁴ is selected from N and CR⁹;

R³ is 4-14 membered heterocycloalkyl;

R⁴ is 4-14 membered heterocycloalkyl;

R⁵ is H;

R⁶, R⁷, R⁸, and R⁹ are each independently selected from H, D, C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), C(O)NR^(c2)R^(d2),NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR^(a1),and NR^(c1)R^(d1); wherein said C₁₋₆ alkyl and 4-10 memberedheterocycloalkyl are each optionally substituted with 1 or 2substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR^(a3),and NR^(c3)R^(d3);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

each R^(c2) and R^(d2) is independently selected from H, C₁₋₆ alkyl, andC₁₋₆ haloalkyl;

each R^(b2) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; and

each R^(a3), R^(c3) and R^(d3) is independently selected from H and C₁₋₆alkyl.

In some embodiments, provided herein is a compound of Formula (I),wherein:

Cy¹ is selected from phenyl and 5-6 membered heteroaryl; wherein the 5-6membered heteroaryl has at least one ring-forming carbon atom and 1, 2,3, or 4 ring-forming heteroatoms independently selected from N, O, andS; and wherein the phenyl and 5-6 membered heteroaryl are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R¹⁰;

R¹ is OR³ or NR⁴R⁵;

R² is H;

A¹ is selected from N and CR⁶;

A² is selected from N and CR⁷;

A³ is selected from N and CR;

A⁴ is selected from N and CR⁹;

R³ is 4-6 membered heterocycloalkyl;

R⁴ is 4-6 membered heterocycloalkyl;

R⁵ is H;

R⁶, R⁷, R⁸, and R⁹ are each independently selected from H, D, C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), C(O)NR^(c2)R^(d2),NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR^(a1), andNR^(c1)R^(d1); wherein said C₁₋₆ alkyl and 4-6 membered heterocycloalkylare each optionally substituted with 1 or 2 substituents independentlyselected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR^(a3), andNR^(c3)R^(d3);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

each R^(c2) and R^(d2) is independently selected from H, C₁₋₆ alkyl, andC₁₋₆ haloalkyl;

each R^(b2) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; and

each R^(a3), R^(c3) and R^(d3) is independently selected from H and C₁₋₆alkyl.

In some embodiments, provided herein is a compound of Formula (I)wherein:

Cy¹ is selected from phenyl and 5-6 membered heteroaryl; wherein the 5-6membered heteroaryl has at least one ring-forming carbon atom and 1, 2,3, or 4 ring-forming heteroatoms independently selected from N, O, andS; and wherein the phenyl and 5-6 membered heteroaryl are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R¹⁰;

R¹ is OR³ or NR⁴R⁵;

R² is H;

A¹ is CR⁶;

A² is CR⁷;

A³ is selected from N and CR⁸;

A⁴ is CR⁹;

R³ is 4-6 membered heterocycloalkyl;

R⁴ is 4-6 membered heterocycloalkyl;

R⁵ is H;

R⁶, R⁷, R⁸, and R⁹ are each independently selected from H, D, C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), C(O)NR^(c2)R^(d2),NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR^(a1), andNR^(c1)R^(d1); wherein said C₁₋₆ alkyl and 4-6 memberedheterocycloalkyl, are each optionally substituted with 1 or 2substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR^(a3), andNR^(c3)R^(d3);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

each R^(c2) and R^(d2) is independently selected from H, C₁₋₆ alkyl, andC₁₋₆ haloalkyl;

each R^(b2) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; and

each R^(a3), R^(c3) and R^(d3) is independently selected from H and C₁₋₆alkyl.

In some embodiments, provided herein is a compound selected from:

-   N-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   4-fluoro-N-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;-   4-fluoro-N,3-dimethyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-4-fluoro-N,3-dimethyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3-cyano-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)—N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;-   (S)-3-cyano-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-5-(6-(1-isopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide;-   (S)-5-(6-(1-isopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide;-   (S)-3,4-difluoro-N-methyl-5-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3,4-difluoro-N-methyl-5-(6-(4-(4-methylpiperazin-1-yl)phenyl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3,4-difluoro-N-methyl-5-(6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide-   (S)-3,4-difluoro-N-methyl-5-(6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide-   (S)-3,4-difluoro-N-methyl-5-(6-(6-methylpyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-4-fluoro-N,3-dimethyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3,4-difluoro-N-methyl-5-(6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)—N-methyl-5-(6-(4-(4-methylpiperazin-1-yl)phenyl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;-   (S)—N-methyl-5-(6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;-   (S)—N-methyl-5-(6-(6-morpholinopyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;-   (S)-5-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide;-   (S)-5-(6-(1-cyclobutyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide;-   (S)-3-(difluoromethyl)-4-fluoro-N-methyl-5-(6-(pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3-(difluoromethyl)-4-fluoro-N-methyl-5-(6-(5-methyl-6-(methylamino)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3-(difluoromethyl)-4-fluoro-5-(6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylbenzamide;-   (S)-3-(difluoromethyl)-4-fluoro-N-methyl-5-(6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3-cyano-N-methyl-5-(6-(pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3-cyano-N-methyl-5-(6-(6-methylpyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3-cyano-N-methyl-5-(6-(5-methylpyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3-cyano-N-methyl-5-(6-(pyridin-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-4-fluoro-3-hydroxy-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;    and-   (S)-3-(6-(1-cyclobutyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methyl-5-(methylsulfonyl)benzamide;

or a pharmaceutically acceptable salt of any of the aforementioned.

In some embodiments, provided herein is a compound selected from:

-   (S)-3-(1H-Indazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine;-   (S)-4-Fluoro-N,3-dimethyl-5-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-4-Fluoro-N,3-dimethyl-5-(6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-4-Fluoro-3-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,5-dimethylbenzamide;-   (S)-3-(6-(1-(2-Cyanoethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-N,5-dimethylbenzamide;-   3-(6-(1-(1,1-Dioxidotetrahydrothiophen-3-yl)-1H-pyrazol-4-yl)-5-(((S)-tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-N,5-dimethylbenzamide;-   (S)-3-(6-(1-(2-(Dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-N,5-dimethylbenzamide;-   (S)-4-Fluoro-3-(6-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,5-dimethylbenzamide;-   4-Fluoro-N,3-dimethyl-5-(6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-5-(((S)-tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-4-Fluoro-N,3-dimethyl-5-(6-(2-methyloxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3-(6-(1-Ethyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-N,5-dimethylbenzamide;-   (S)-4-Fluoro-N,3-dimethyl-5-(6-(pyridazin-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3-(5-(Ethylsulfonyl)-2,3-difluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-N-(tetrahydrofuran-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine;-   (S)-3-(5-(Ethylsulfonyl)-2,3-difluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine;-   (S)-3-(Difluoromethyl)-4-fluoro-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3-(Difluoromethyl)-5-(6-(1-ethyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-N-methylbenzamide;-   3-(Difluoromethyl)-4-fluoro-N-methyl-5-(6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-5-(((S)-tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3-(Difluoromethyl)-4-fluoro-5-(6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylbenzamide;-   (S)-3-(3-(1H-Pyrazol-3-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine;-   (S)-3,4-Difluoro-N-methyl-5-(6-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3-(6-(1-Ethyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4,5-difluoro-N-methylbenzamide;-   (S)-3,4-Difluoro-N-methyl-5-(6-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3,4-Difluoro-N-methyl-5-(6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)-3,4-Difluoro-5-(6-(1-isopropyl-2-oxo-1,2-dihydropyridin-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylbenzamide;-   (S)-3,4-Difluoro-5-(6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylbenzamide;-   (S)-3,4-Difluoro-N-methyl-5-(6-(2-methyloxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;-   (S)—N-Methyl-5-(6-(1-methyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;-   (S)—N-Methyl-5-(6-(2-methyl-2H-1,2,3-triazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;-   (S)—N-Ethyl-5-(6-(1-methyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;-   (S)—N-Isopropyl-5-(6-(1-methyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;-   (S)-5-(6-(1-Isopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(methyl-d₃)nicotinamide;-   4-Fluoro-3-(6-(1-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(((S)-tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-methyl-N-(methyl-d₃)benzamide;-   4-Fluoro-3-(6-(1-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(((S)-tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,5-dimethylbenzamide;-   3-(6-(6-(((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)pyridin-3-yl)-5-(((S)-tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-(difluoromethyl)-4-fluoro-N-(methyl-d₃)benzamide;-   (S)-4-Fluoro-3-(6-(2-(1-isopropylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-5-methyl-N-(methyl-d₃)benzamide;-   (S)-4-Fluoro-3-(6-(2-(1-isopropylpiperidin-4-yl)oxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-5-methyl-N-(methyl-d₃)benzamide;-   (S)-4-Fluoro-3-(6-(2-(4-fluoro-1-methylpiperidin-4-yl)oxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,5-dimethylbenzamide;    and-   (S)-4-Fluoro-N,3-dimethyl-5-(6-(2-(4-methylpiperazin-1-yl)oxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;

or a pharmaceutically acceptable salt of any of the aforementioned.

In some embodiments, or a pharmaceutically acceptable salt thereof,wherein:

Cy¹ is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; whereineach 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3 or 4 substituents independently selected from R¹⁰;

R¹ is OR³ or NR⁴R⁵;

R² is selected from H, D, and halo;

A¹ is CR⁶;

A² is CR⁷;

A³ is selected from N and CR⁸;

A⁴ is CR⁹;

R³ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-14membered heterocycloalkyl, wherein said C₃₋₁₀ cycloalkyl, and 4-14membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R³⁰;

R⁴ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, and4-14 membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, and 4-14 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁴⁰;

R⁵ is H;

each R⁶, R⁷, R⁸, and R⁹ is independently selected from H, D, C₁₋₆ alkyl,C₁₋₆ haloalkyl, 5-10 membered heteroaryl, halo, CN, OR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), and S(O)₂R^(b1); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, and 4-10 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, halo, D, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), NR^(c3)R^(d3), and S(O)₂R^(b3); wherein said C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a5), and NR^(c5)R^(d5).

each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a4), and NR^(c4)R^(d4);

each R³⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl halo,D, CN, OR^(a6), and NR^(c6)R^(d6);

each R⁴⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a7), and NR^(c7)R^(d7);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²⁰;

each R^(b2) is independently selected from C₁₋₆ alkyl, and C₁₋₆haloalkyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; each R^(b3) is independently selected fromC₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

each R^(a5), R^(c5) and R^(d)s, is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

each R^(a6), R^(c6) and R^(d6), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; and

each R^(a7), R^(c7) and R^(d7), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl.

In some embodiments, or a pharmaceutically acceptable salt thereof,wherein:

Cy¹ is selected from phenyl and 5-10 membered heteroaryl; wherein each5-10 membered heteroaryl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; and wherein the phenyl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2 or 3 substituents independentlyselected from R¹⁰;

R¹ is OR³ or NR⁴R⁵;

R² is H;

A1 is CR⁶;

A2 is CR⁷;

A3 is selected from N and CR⁸;

A4 is CR⁹;

R³ is 4-6 membered heterocycloalkyl;

R⁴ is 4-6 membered heterocycloalkyl;

R⁵ is H;

R⁶, R⁷, R⁸, and R⁹ is independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, 5-6 membered heteroaryl, halo, CN, OR^(a2),C(O)NR^(c2)R^(d2), NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a1), andNR^(c1)R^(d1); wherein said C₁₋₆ alkyl and C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl, are each optionally substituted with 1 or 2substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, halo, D, CN, OR^(a3), C(O)NR^(c3)R^(d3), and NR^(c3)R^(d3).

each R²⁰ is independently selected from D;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, is optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰;

each R^(b2) is independently selected from C₁₋₆ alkyl, and C₁₋₆haloalkyl; and

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

At various places in the present specification various aryl, heteroaryl,cycloalkyl, and heterocycloalkyl rings are described. Unless otherwisespecified, these rings can be attached to the rest of the molecule atany ring member as permitted by valency. For example, the term “apyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl,or pyridin-4-yl ring.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety independently selectedfrom the group defining the variable. For example, where a structure isdescribed having two R groups that are simultaneously present on thesame compound, the two R groups can represent different moietiesindependently selected from the group defined for R.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. A single divalent substituent,e.g., oxo, can replace two hydrogen atoms.

As used herein, the term “C_(i-j),” where i and j are integers, employedin combination with a chemical group, designates a range of the numberof carbon atoms in the chemical group with i-j defining the range. Forexample, C₁₋₆ alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6carbon atoms.

As used herein, the term “alkyl,” employed alone or in combination withother terms, refers to a saturated hydrocarbon group that may bestraight-chain or branched. An alkyl group formally corresponds to analkane with one C—H bond replaced by the point of attachment of thealkyl group to the remainder of the compound. In some embodiments, thealkyl group contains 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples ofalkyl moieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl, and the like. In some embodiments, the alkylgroup is methyl, ethyl, or propyl.

As used herein, the term “C_(i-j) alkylene,” employed alone or incombination with other terms, means a saturated divalent linkinghydrocarbon group that may be straight-chain or branched, having i to jcarbons. In some embodiments, the alkylene group contains from 1 to 4carbon atoms, from 1 to 3 carbon atoms, or from 1 to 2 carbon atoms.Examples of alkylene moieties include, but are not limited to, chemicalgroups such as methylene, ethylene, 1,1-ethylene, 1,2-ethylene,1,3-propylene, 1,2-propylene, 1,1-propylene, isopropylene, and the like.

As used herein, “alkenyl,” employed alone or in combination with otherterms, refers to a straight-chain or branched hydrocarbon groupcorresponding to an alkyl group having one or more carbon-carbon doublebonds. An alkenyl group formally corresponds to an alkene with one C—Hbond replaced by the point of attachment of the alkenyl group to theremainder of the compound. In some embodiments, the alkenyl moietycontains 2 to 6 or 2 to 4 carbon atoms. Example alkenyl groups include,but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl,sec-butenyl, and the like.

As used herein, “alkynyl,” employed alone or in combination with otherterms, refers to a straight-chain or branched hydrocarbon groupcorresponding to an alkyl group having one or more carbon-carbon triplebonds. An alkynyl group formally corresponds to an alkyne with one C—Hbond replaced by the point of attachment of the alkyl group to theremainder of the compound. In some embodiments, the alkynyl moietycontains 2 to 6 or 2 to 4 carbon atoms. Example alkynyl groups include,but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like.

As used herein, “halo” or “halogen”, employed alone or in combinationwith other terms, includes fluoro, chloro, bromo, and iodo. In someembodiments, halo is F or Cl. In some embodiments, halo is F.

As used herein, the term “haloalkyl,” employed alone or in combinationwith other terms, refers to an alkyl group in which one or more of thehydrogen atoms has been replaced by a halogen atom, having up to thefull valency of halogen atom substituents, which may either be the sameor different. In some embodiments, the halogen atoms are fluoro atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms. Example haloalkyl groups include CF₃, C₂F₅, CHF₂, CCl₃,CHCl₂, C₂Cl₅, and the like.

As used herein, the term “alkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-alkyl. In some embodiments,the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examplealkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like. In some embodiments, alkoxy ismethoxy.

As used herein, “haloalkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-(haloalkyl). In someembodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.An example haloalkoxy group is —OCF₃.

As used herein, “amino,” employed alone or in combination with otherterms, refers to NH₂.

As used herein, the term “alkylamino,” employed alone or in combinationwith other terms, refers to a group of formula —NH(alkyl). In someembodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms.Example alkylamino groups include methylamino, ethylamino, propylamino(e.g., n-propylamino and isopropylamino), and the like.

As used herein, the term “dialkylamino,” employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂.Example dialkylamino groups include dimethylamino, diethylamino,dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and thelike. In some embodiments, each alkyl group independently has 1 to 6 or1 to 4 carbon atoms.

As used herein, the term “alkylthio,” employed alone or in combinationwith other terms, refers to a group of formula —S-alkyl. In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “cycloalkyl,” employed alone or in combinationwith other terms, refers to a non-aromatic cyclic hydrocarbon includingcyclized alkyl and alkenyl groups. The term “C_(n-m) cycloalkyl” refersto a cycloalkyl that has n to m ring member carbon atoms. Cycloalkylgroups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused,bridged, or spiro rings) ring systems. Also included in the definitionof cycloalkyl are moieties that have one or more aromatic rings (e.g.,aryl or heteroaryl rings) fused (i.e., having a bond in common with) tothe cycloalkyl ring, for example, benzo derivatives of cyclopentane,cyclohexene, cyclohexane, and the like, or pyrido derivatives ofcyclopentane or cyclohexane. A cycloalkyl group containing a fusedaromatic ring can be attached through any ring-forming atom including aring-forming atom of the fused aromatic ring. Ring-forming carbon atomsof a cycloalkyl group can be optionally substituted by oxo. Cycloalkylgroups also include cycloalkylidenes. The term “cycloalkyl” alsoincludes bridgehead cycloalkyl groups (e.g., non-aromatic cyclichydrocarbon moieties containing at least one bridgehead carbon, such asadmantan-1-yl) and spirocycloalkyl groups (e.g., non-aromatichydrocarbon moieties containing at least two rings fused at a singlecarbon atom, such as spiro[2.5]octane and the like). In someembodiments, the cycloalkyl group has 3 to 10 ring members, or 3 to 7ring members, or 3 to 6 ring members. In some embodiments, thecycloalkyl group is monocyclic or bicyclic. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is a C₃₋₇ monocyclic cycloalkyl group. Example cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl,octahydronaphthalenyl, indanyl, and the like. In some embodiments, thecycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, the term “heterocycloalkyl,” employed alone or incombination with other terms, refers to a non-aromatic ring or ringsystem, which may optionally contain one or more alkenylene oralkynylene groups as part of the ring structure, which has at least oneheteroatom ring member independently selected from nitrogen, sulfur,oxygen, and phosphorus, and which has 4-14 ring members, 4-10 ringmembers, 4-7 ring members, or 4-6 ring members. Included within the term“heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-memberedheterocycloalkyl groups. Heterocycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused, bridged, or spiro rings) orspirocyclic ring systems. In some embodiments, the heterocycloalkylgroup is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatomsindependently selected from nitrogen, sulfur and oxygen. Also includedin the definition of heterocycloalkyl are moieties that have one or morearomatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having abond in common with) to the non-aromatic heterocycloalkyl ring, forexample, 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkylgroups can also include bridgehead heterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least one bridgehead atom, such asazaadmantan-1-yl and the like) and spiroheterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least two rings fused at a singleatom, such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and the like). Insome embodiments, the heterocycloalkyl group has 3 to 10 ring-formingatoms, 4 to 10 ring-forming atoms, or 3 to 8 ring forming atoms. In someembodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atomsor heteroatoms in the ring(s) of the heterocycloalkyl group can beoxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or otheroxidized linkage) or a nitrogen atom can be quaternized. In someembodiments, the heterocycloalkyl portion is a C₂₋₇ monocyclicheterocycloalkyl group. In some embodiments, the heterocycloalkyl groupis a morpholine ring, pyrrolidine ring, piperazine ring, piperidinering, dihydropyran ring, tetrahydropyran ring, tetrahyropyridine,azetidine ring, or tetrahydrofuran ring. In some embodiments, theheterocycloalkyl is a 4-7 membered heterocycloalkyl moiety having carbonand 1, 2, or 3 heteroatoms independently selected from N, O and S. Insome embodiments, the heterocycloalkyl is 4-10 membered heterocycloalkylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., having 2 fusedrings) aromatic hydrocarbon moiety, such as, but not limited to, phenyl,1-naphthyl, 2-naphthyl, and the like. In some embodiments, aryl groupshave from 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments,the aryl group is a monocyclic or bicyclic group. In some embodiments,the aryl group is phenyl.

As used herein, the term “heteroaryl” or “heteroaromatic” employed aloneor in combination with other terms, refers to a monocyclic or polycyclic(e.g., having 2 or 3 fused rings) aromatic hydrocarbon moiety, havingone or more heteroatom ring members independently selected fromnitrogen, sulfur and oxygen. In some embodiments, the heteroaryl groupis a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatomsindependently selected from nitrogen, sulfur and oxygen. Exampleheteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl,thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl,benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl,1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl,indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl or the like. The carbon atoms or heteroatoms inthe ring(s) of the heteroaryl group can be oxidized to form a carbonyl,an N-oxide, or a sulfonyl group (or other oxidized linkage) or anitrogen atom can be quaternized, provided the aromatic nature of thering is preserved. In one embodiment the heteroaryl group is a 5 to 10membered heteroaryl group. In another embodiment the heteroaryl group isa 5 to 6 membered heteroaryl group. In some embodiments, the heteroarylis a 5-6 membered heteroaryl moiety having carbon and 1, 2, or 3heteroatoms independently selected from N, O and S. In some embodiments,the heteroaryl is a 5-10 membered heteroaryl moiety having carbon and 1,2, or 3 heteroatoms independently selected from N, O and S. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, no more than 2 heteroatoms of a 5-membered heteroarylmoiety are N.

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group. Insome embodiments, heterocyclic groups may be optionally substituted by 1or 2 oxo (═O) substituents.

The term “oxidized” in reference to a ring-forming N atom refers to aring-forming N-oxide.

The term “oxidized” in reference to a ring-forming S atom refers to aring-forming sulfonyl or ring-forming sulfinyl.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out bymethods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids. Other resolvingagents suitable for fractional crystallization methods includestereoisomerically pure forms of methylbenzylamine (e.g., S and R forms,or diastereomerically pure forms), 2-phenylglycinol, norephedrine,ephedrine, N-methylephedrine, cyclohexylethylamine,1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention also include all isotopes of atoms occurringin the intermediates or final compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. For example,isotopes of hydrogen include tritium and deuterium. One or moreconstituent atoms of the compounds of the invention can be replaced orsubstituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art (Deuterium Labeling in OrganicChemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts,1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau,Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007,7744-7765; The Organic Chemistry of Isotopic Labelling by James R.Hanson, Royal Society of Chemistry, 2011). Isotopically labeledcompounds can used in various studies such as NMR spectroscopy,metabolism experiments, and/or assays.

Substitution with heavier isotopes such as deuterium, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. (A. Kerekes et. al. J.Med. Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm.2015, 58, 308-312).

The term, “compound,” as used herein is meant to include allstereoisomers, geometric iosomers, tautomers, and isotopes of thestructures depicted. The term is also meant to refer to compounds of theinventions, regardless of how they are prepared, e.g., synthetically,through biological process (e.g., metabolism or enzyme conversion), or acombination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,in the form of hydrates and solvates) or can be isolated. When in thesolid state, the compounds described herein and salts thereof may occurin various forms and may, e.g., take the form of solvates, includinghydrates. The compounds may be in any solid state form, such as apolymorph or solvate, so unless clearly indicated otherwise, referencein the specification to compounds and salts thereof should be understoodas encompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the non-toxic salts ofthe parent compound formed, for example, from non-toxic inorganic ororganic acids. The pharmaceutically acceptable salts of the presentinvention can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g.,methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) arepreferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); br (broad); Cbz (carboxybenzyl); calc. (calculated);d (doublet); dd (doublet of doublets); DCM (dichloromethane); DEAD(diethyl azodicarboxylate); DIAD (N,N′-diisopropyl azidodicarboxylate);DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); Et(ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquidchromatography—mass spectrometry); m (multiplet); M (molar); mCPBA(3-chloroperoxybenzoic acid); MgSO₄ (magnesium sulfate); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); N (normal); NaHCO₃ (sodium bicarbonate); NaOH (sodiumhydroxide); Na₂SO₄ (sodium sulfate); NH₄Cl (ammonium chloride); NH₄OH(ammonium hydroxide); NIS (N-iodosuccinimide); nM (nanomolar); NMR(nuclear magnetic resonance spectroscopy); OTf(trifluoromethanesulfonate); Pd (palladium); Ph (phenyl); pM(picomolar); PMB (para-methoxybenzyl), POCl₃ (phosphoryl chloride);RP-HPLC (reverse phase high performance liquid chromatography); s(singlet); SEM (2-trimethylsilylethoxymethyl); t (triplet or tertiary);TBS (tert-butyldimethylsilyl); tert (tertiary); tt (triplet oftriplets); t-Bu (tert-butyl); TFA (trifluoroacetic acid); THF(tetrahydrofuran); μg (microgram(s)); μL (microliter(s)); μM(micromolar); wt % (weight percent).

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and according to variouspossible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), ormass spectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

The expressions, “ambient temperature,” “room temperature,” and “r.t.”,as used herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Compounds of Formula (I) can be prepared as shown in Scheme 1.Halogenation of commercially available heterocycles 1-1 (whereinZ=halogen (F, Cl, Br, I) or pseudohalogen (e.g., OTf)) with a suitablehalogenating reagent (e.g., NBS, NCS, etc.) affords intermediates 1-2.Nucleophilic aromatic substitution with ammonia then affords amines 1-3,which can undergo selective halogenation to provide intermediates 1-4.Removal of the amino group under reductive deamination conditions (e.g.alkyl nitrite in an appropriate solvent at elevated temperature) affordsintermediates 1-5, which can undergo selective cross-coupling with M-Cy¹(wherein M is B(OH)₂, Bpin, BF₃K, Sn(Bu)₃, or Zn) to give intermediates1-6. Nucleophilic aromatic substitution with R^(1′)—XH (wherein X═O orNH) provides intermediates 1-7, which can undergo cross-coupling withintermediates 1-8 under standard Suzuki conditions (Tetrahedron 2002,58, 9633-9695) (e.g., in the presence of a palladium catalyst, such as[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complexwith dichloromethane orbis(di-tert-butyl(4-dimethyl-aminophenyl)phosphine)-dichloropalladium(II)and a base (e.g., a carbonate base or cesium fluoride)), or standardStille conditions (ACS Catalysis 2015, 5, 3040-3053) (e.g., in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)-palladium(0)), or standard Negishiconditions (ACS Catalysis 2016, 6, 1540-1552) (e.g., in the presence ofa palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0)or [1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium (II)), toafford compounds of the Formula Ia.

Compounds of Formula I can also be prepared as shown in Scheme 2. Fromintermediates 1-5 (Scheme 1), nucleophilic aromatic substitution withR^(1′)—XH (wherein X═O or NH) provides intermediates 2-1, which canundergo selective cross-coupling with intermediates 1-8 to affordcompounds 2-2. Cross coupling of 2-2 with M-Cy¹ then affords compoundsof Formula Ib.

Methods of Use

Compounds of the present disclosure can inhibit the activity of the FGFRenzyme. For example, compounds of the present disclosure can be used toinhibit activity of an FGFR enzyme in a cell or in an individual orpatient in need of inhibition of the enzyme by administering aninhibiting amount of one or more compounds of the present disclosure tothe cell, individual, or patient.

As FGFR inhibitors, the compounds of the present disclosure are usefulin the treatment of various diseases associated with abnormal expressionor activity of the FGFR enzyme or FGFR ligands. Compounds which inhibitFGFR will be useful in providing a means of preventing the growth orinducing apoptosis in tumors, particularly by inhibiting angiogenesis.It is therefore anticipated that compounds of the present disclosurewill prove useful in treating or preventing proliferative disorders suchas cancers. In particular, tumors with activating mutants of receptortyrosine kinases or upregulation of receptor tyrosine kinases may beparticularly sensitive to the inhibitors.

In certain embodiments, the disclosure provides a method for treating aFGFR-mediated disorder in a patient in need thereof, comprising the stepof administering to said patient a compound according to the invention,or a pharmaceutically acceptable composition thereof.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

In some embodiments, said cancer is selected from hepatocellular cancer,bladder cancer, breast cancer, cervical cancer, colorectal cancer,endometrial cancer, gastric cancer, head and neck cancer, kidney cancer,liver cancer, cholangiocarcinoma, lung cancer, ovarian cancer, prostatecancer, esophageal cancer, gall bladder cancer, pancreatic cancer,thyroid cancer, skin cancer, leukemia, multiple myeloma, chroniclymphocytic lymphoma, adult T cell leukemia, B-cell lymphoma, acutemyelogenous leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom'sMacroglubulinemia, hairy cell lymphoma, Burkett's lymphoma,glioblastoma, melanoma, and rhabdosarcoma. In some embodiments, saidcancer is selected from bladder cancer, breast cancer, colorectalcancer, endometrial cancer, gastric cancer, head and neck cancer, kidneycancer, liver cancer, cholangiocarcinoma, lung cancer, ovarian cancer,pancreatic cancer, glioblastoma, melanoma, and rhabdosarcoma.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET), 8p11myeloproliferative syndrome), myelodysplasia syndrome (MDS), T-cellacute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-celllymphoma, adult T-cell leukemia, Waldenstrom's Macroglubulinemia, hairycell lymphoma, marginal zone lymphoma, chronic myelogenic lymphoma andBurkitt's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma,lymphosarcoma, leiomyosarcoma, and teratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, mesothelioma, pavicellular and non-pavicellularcarcinoma, bronchial adenoma and pleuropulmonary blastoma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (exocrinepancreatic carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma,gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma,lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma,lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubularadenoma, villous adenoma, hamartoma, leiomyoma), colorectal cancer, gallbladder cancer and anal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma], renal cell carcinoma),bladder and urethra (squamous cell carcinoma, transitional cellcarcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma) and urothelial carcinoma.

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors, neuro-ectodermal tumors), and spinal cord(neurofibroma, meningioma, glioma, sarcoma), neuroblastoma,Lhermitte-Duclos disease and pineal tumors.

Exemplary gynecological cancers include cancers of the breast (ductalcarcinoma, lobular carcinoma, breast sarcoma, triple-negative breastcancer, HER2-positive breast cancer, inflammatory breast cancer,papillary carcinoma), uterus (endometrial carcinoma), cervix (cervicalcarcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma(serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.

Exemplary head and neck cancers include glioblastoma, melanoma,rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas,adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer,nasal and paranasal cancers, thyroid and parathyroid cancers, tumors ofthe eye, tumors of the lips and mouth and squamous head and neck cancer.

The compounds of the present disclosure can also be useful in theinhibition of tumor metastases.

In addition to oncogenic neoplasms, the compounds of the invention areuseful in the treatment of skeletal and chondrocyte disorders including,but not limited to, achrondroplasia, hypochondroplasia, dwarfism,thanatophoric dysplasia (TD) (clinical forms TD I and TD II), Apertsyndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevensoncutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosissyndromes. In some embodiments, the present disclosure provides a methodfor treating a patient suffering from a skeletal and chondrocytedisorder.

In some embodiments, compounds described herein can be used to treatAlzheimer's disease, HIV, or tuberculosis.

As used herein, the term “8p11 myeloproliferative syndrome” is meant torefer to myeloid/lymphoid neoplasms associated with eosinophilia andabnormalities of FGFR1.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the FGFR enzyme with a compound described hereinincludes the administration of a compound described herein to anindividual or patient, such as a human, having FGFR, as well as, forexample, introducing a compound described herein into a samplecontaining a cellular or purified preparation containing the FGFRenzyme.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent such as an amountof any of the solid forms or salts thereof as disclosed herein thatelicits the biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician. An appropriate“effective” amount in any individual case may be determined usingtechniques known to a person skilled in the art.

The phrase “pharmaceutically acceptable” is used herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, immunogenicity or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

As used herein, the phrase “pharmaceutically acceptable carrier orexcipient” refers to a pharmaceutically-acceptable material,composition, or vehicle, such as a liquid or solid filler, diluent,solvent, or encapsulating material. Excipients or carriers are generallysafe, non-toxic and neither biologically nor otherwise undesirable andinclude excipients or carriers that are acceptable for veterinary use aswell as human pharmaceutical use. In one embodiment, each component is“pharmaceutically acceptable” as defined herein. See, e.g., Remington:The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the AmericanPharmaceutical Association: 2009; Handbook of Pharmaceutical Additives,3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., 2009.

As used herein, the term “treating” or “treatment” refers to inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology) orameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment (while the embodimentsare intended to be combined as if written in multiply dependent form).Conversely, various features of the invention which are, for brevity,described in the context of a single embodiment, can also be providedseparately or in any suitable subcombination.

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, anti-viral agents, chemotherapeutics or otheranti-cancer agents, immune enhancers, immunosuppressants, radiation,anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF,etc.), and/or tyrosine kinase inhibitors can be used in combination withcompounds described herein for treatment of FGFR-associated diseases,disorders or conditions, or diseases or conditions as described herein.The agents can be combined with the present compounds in a single dosageform, or the agents can be administered simultaneously or sequentiallyas separate dosage forms.

Compounds described herein can be used in combination with one or moreother kinase inhibitors for the treatment of diseases, such as cancer,that are impacted by multiple signaling pathways. For example, acombination can include one or more inhibitors of the following kinasesfor the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, Pim, PKA, PKG,PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR,HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT,FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron,Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3,EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL,ALK and B-Raf Additionally, the solid forms of the FGFR inhibitor asdescribed herein can be combined with inhibitors of kinases associatedwith the PIK3/Akt/mTOR signaling pathway, such as PI3K, Akt (includingAkt1, Akt2 and Akt3) and mTOR kinases.

In some embodiments, compounds described herein can be used incombination with one or more inhibitors of the enzyme or proteinreceptors such as HPK1, SBLB, TUT4, A2A/A2B, CD47, CDK2, STING, ALK2,LIN28, ADAR1, MAT2a, RIOK1, HDAC8, WDR5, SMARCA2, and DCLK1 for thetreatment of diseases and disorders. Exemplary diseases and disordersinclude cancer, infection, inflammation and neurodegenerative disorders.

In some embodiments, compounds described herein can be used incombination with a therapeutic agent that targets an epigeneticregulator. Examples of epigenetic regulators include bromodomaininhibitors, the histone lysine methyltransferases, histone argininemethyl transferases, histone demethylases, histone deacetylases, histoneacetylases, and DNA methyltransferases. Histone deacetylase inhibitorsinclude, e.g., vorinostat.

For treating cancer and other proliferative diseases, compoundsdescribed herein can be used in combination with targeted therapies,including JAK kinase inhibitors (Ruxolitinib, additional JAK1/2 andJAK1-selective, baricitinib or INCB39110), Pim kinase inhibitors (e.g.,LGH447, INCB053914 and SGI-1776), PI3 kinase inhibitors includingPI3K-delta selective and broad spectrum PI3K inhibitors (e.g., INCB50465and INCB54707), PI3K-gamma inhibitors such as PI3K-gamma selectiveinhibitors, MEK inhibitors, CSF1R inhibitors (e.g., PLX3397 andLY3022855), TAM receptor tyrosine kinases inhibitors (Tyro-3, Axl, andMer; e.g., INCB81776), angiogenesis inhibitors, interleukin receptorinhibitors, Cyclin Dependent kinase inhibitors, BRAF inhibitors, mTORinhibitors, proteasome inhibitors (Bortezomib, Carfilzomib),HDAC-inhibitors (panobinostat, vorinostat), DNA methyl transferaseinhibitors, dexamethasone, bromo and extra terminal family membersinhibitors (for example, bromodomain inhibitors or BET inhibitors, suchas OTX015, CPI-0610, INCB54329 or INCB57643), LSD1 inhibitors (e.g.,GSK2979552, INCB59872 and INCB60003), arginase inhibitors (e.g.,INCB1158), indoleamine 2,3-dioxygenase inhibitors (e.g., epacadostat,NLG919 or BMS-986205), PARP inhibiors (e.g., olaparib or rucaparib), andinhibitors of BTK such as ibrutinib. For treating cancer and otherproliferative diseases, compounds described herein can be used incombination with targeted therapies, including c-MET inhibitors (e.g.,capmatinib), an ALK2 inhibitor (e.g., INCB00928), or combinationsthereof.

For treating cancer and other proliferative diseases, compoundsdescribed herein can be used in combination with chemotherapeuticagents, agonists or antagonists of nuclear receptors, or otheranti-proliferative agents. Compounds described herein can also be usedin combination with a medical therapy such as surgery or radiotherapy,e.g., gamma-radiation, neutron beam radiotherapy, electron beamradiotherapy, proton therapy, brachytherapy, and systemic radioactiveisotopes.

Examples of suitable chemotherapeutic agents include any of abarelix,abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, amidox, amsacrine, anastrozole,aphidicolon, arsenic trioxide, asparaginase, axitinib, azacitidine,bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide,bleomycin, bortezombi, bortezomib, brivanib, buparlisib, busulfanintravenous, busulfan oral, calusterone, camptosar, capecitabine,carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin,cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine,dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib,dactinomycin, daunorubicin, decitabine, degarelix, denileukin,denileukin diftitox, deoxycoformycin, dexrazoxane, didox, docetaxel,doxorubicin, droloxafine, dromostanolone propionate, eculizumab,enzalutamide, epidophyllotoxin, epirubicin, epothilones, erlotinib,estramustine, etoposide phosphate, etoposide, exemestane, fentanylcitrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide,fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lonafarnib, lomustine, meclorethamine,megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, navelbene, necitumumab, nelarabine, neratinib,nilotinib, nilutamide, niraparib, nofetumomab, oserelin, oxaliplatin,paclitaxel, pamidronate, panitumumab, panobinostat, pazopanib,pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,pilaralisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone,procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib,reloxafine, revlimid, rituximab, rucaparib, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur,temozolomide, teniposide, testolactone, tezacitabine, thalidomide,thioguanine, thiotepa, tipifarnib, topotecan, toremifene, tositumomab,trastuzumab, tretinoin, triapine, trimidox, triptorelin, uracil mustard,valrubicin, vandetanib, vinblastine, vincristine, vindesine,vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

In some embodiments, compounds described herein can be used incombination with immune checkpoint inhibitors. In some embodiments, theinhibitor of an immune checkpoint molecule is an inhibitor of CD19,e.g., an anti-CD19 antibody. In some embodiments, the anti-CD19 antibodyis tafasitamab. In some embodiments, the anti-PD-1 monoclonal antibodyis MGA012 (retifanlimab). Exemplary immune checkpoint inhibitors includeinhibitors against immune checkpoint molecules such as CD27, CD28, CD40,CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma,TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4,BTLA, CTLA-4, LAG3 (e.g., INCAGN2385), TIM3 (e.g., INCB2390), VISTA,PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpointmolecule is a stimulatory checkpoint molecule selected from CD27, CD28,CD40, ICOS, OX40 (e.g., INCAGN1949), GITR (e.g., INCAGN1876) and CD137.In some embodiments, the immune checkpoint molecule is an inhibitorycheckpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO,KIR, LAG3, PD-1, TIM3, and VISTA. In some embodiments, the compoundsprovided herein can be used in combination with one or more agentsselected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule PD-L1 inhibitor. In some embodiments, the small moleculePD-L1 inhibitor has an IC50 less than 1 μM, less than 100 nM, less than10 nM or less than 1 nM in a PD-L1 assay described in US PatentPublication Nos. US 20170107216, US 20170145025, US 20170174671, US20170174679, US 20170320875, US 20170342060, US 20170362253, and US20180016260, each of which is incorporated by reference in its entiretyfor all purposes.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is MGA012, nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001,ipilumimab or AMP-224. In some embodiments, the anti-PD-1 monoclonalantibody is nivolumab or pembrolizumab. In some embodiments, theanti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD1antibody is nivolumab. In some embodiments, the anti-PD-1 monoclonalantibody is MGA012. In some embodiments, the anti-PD1 antibody isSHR-1210. Other anti-cancer agent(s) include antibody therapeutics suchas 4-1BB (e.g. urelumab, utomilumab.

In some embodiments, the compounds of the disclosure can be used incombination with INCB086550.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of 20 GITR, e.g., an anti-GITR antibody. In someembodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876,MK-1248, AMG228, BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916,PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40Lfusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.

In some embodiments, the compounds described herein can be used incombination with one or more agents for the treatment of diseases suchas cancer. In some embodiments, the agent is an alkylating agent, aproteasome inhibitor, a corticosteroid, or an immunomodulatory agent.Examples of an alkylating agent include cyclophosphamide (CY), melphalan(MEL), and bendamustine. In some embodiments, the proteasome inhibitoris carfilzomib. In some embodiments, the corticosteroid is dexamethasone(DEX). In some embodiments, the immunomodulatory agent is lenalidomide(LEN) or pomalidomide (POM).

Suitable antiviral agents contemplated for use in combination withcompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′, 3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

Suitable agents for use in combination with compounds described hereinfor the treatment of cancer include chemotherapeutic agents, targetedcancer therapies, immunotherapies or radiation therapy. Compoundsdescribed herein may be effective in combination with antihormonalagents for treatment of breast cancer and other tumors. Suitableexamples are anti-estrogen agents including but not limited to tamoxifenand toremifene, aromatase inhibitors including but not limited toletrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g.prednisone), progestins (e.g. megastrol acetate), and estrogen receptorantagonists (e.g. fulvestrant). Suitable anti-hormone agents used fortreatment of prostate and other cancers may also be combined withcompounds described herein. These include anti-androgens including butnot limited to flutamide, bicalutamide, and nilutamide, luteinizinghormone-releasing hormone (LHRH) analogs including leuprolide,goserelin, triptorelin, and histrelin, LHRH antagonists (e.g.degarelix), androgen receptor blockers (e.g. enzalutamide) and agentsthat inhibit androgen production (e.g. abiraterone).

The compounds described herein may be combined with or in sequence withother agents against membrane receptor kinases especially for patientswho have developed primary or acquired resistance to the targetedtherapy. These therapeutic agents include inhibitors or antibodiesagainst EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3 and againstcancer-associated fusion protein kinases such as Bcr-Abl and EML4-Alk.Inhibitors against EGFR include gefitinib and erlotinib, and inhibitorsagainst EGFR/Her2 include but are not limited to dacomitinib, afatinib,lapitinib and neratinib. Antibodies against the EGFR include but are notlimited to cetuximab, panitumumab and necitumumab. Inhibitors of c-Metmay be used in combination with FGFR inhibitors. These includeonartumzumab, tivantnib, and INC-280.

Agents against Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib,and ponatinib and those against Alk (or EML4-ALK) include crizotinib.Angiogenesis inhibitors may be efficacious in some tumors in combinationwith FGFR inhibitors. These include antibodies against VEGF or VEGFR orkinase inhibitors of VEGFR.

Antibodies or other therapeutic proteins against VEGF includebevacizumab and aflibercept. Inhibitors of VEGFR kinases and otheranti-angiogenesis inhibitors include but are not limited to sunitinib,sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, andvandetanib Activation of intracellular signaling pathways is frequent incancer, and agents targeting components of these pathways have beencombined with receptor targeting agents to enhance efficacy and reduceresistance. Examples of agents that may be combined with compoundsdescribed herein include inhibitors of the PI3K-AKT-mTOR pathway,inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway, andinhibitors of protein chaperones and cell cycle progression.

Agents against the PI3 kinase include but are not limited topilaralisib,idelalisib, buparlisib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus may be combined with FGFR inhibitors. Othersuitable examples include but are not limited to vemurafenib anddabrafenib (Raf inhibitors) and trametinib, selumetinib and GDC-0973(MEK inhibitors). Inhibitors of one or more JAKs (e.g., ruxolitinib,baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), HDACs (e.g., panobinostat), PARP (e.g.,olaparib), and proteasomes (e.g., bortezomib, carfilzomib) can also becombined with compounds described herein. In some embodiments, the JAKinhibitor is selective for JAK1 over JAK2 and JAK3.

Other suitable agents for use in combination with compounds describedherein include chemotherapy combinations such as platinum-based doubletsused in lung cancer and other solid tumors (cisplatin or carboplatinplus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin orcarboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed)or gemcitabine plus paclitaxel bound particles (Abraxane®).

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Other suitable agents for use in combination with compounds describedherein include steroids including 17 alpha-ethinylestradiol,diethylstilbestrol, testosterone, prednisone, fluoxymesterone,methylprednisolone, methyltestosterone, prednisolone, triamcinolone,chlorotrianisene, hydroxyprogesterone, aminoglutethimide, andmedroxyprogesteroneacetate.

Other suitable agents for use in combination with compounds describedherein include: dacarbazine (DTIC), optionally, along with otherchemotherapy drugs such as carmustine (BCNU) and cisplatin; the“Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin andtamoxifen; a combination of cisplatin, vinblastine, and DTIC; ortemozolomide. Compounds described herein may also be combined withimmunotherapy drugs, including cytokines such as interferon alpha,interleukin 2, and tumor necrosis factor (TNF) in.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin,mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB, PD-L1 and PD-1 antibodies, or antibodies to cytokines(IL-10, TGF-β, etc.).

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). Non-limiting examples of tumorvaccines that can be used include peptides of melanoma antigens, such aspeptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, ortumor cells transfected to express the cytokine GM-CSF.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, compounds described herein can beadministered in the form of pharmaceutical compositions which refers toa combination of one or more compounds described herein, and at leastone pharmaceutically acceptable carrier or excipient. These compositionscan be prepared in a manner well known in the pharmaceutical art, andcan be administered by a variety of routes, depending upon whether localor systemic treatment is desired and upon the area to be treated.Administration may be topical (including ophthalmic and to mucousmembranes including intranasal, vaginal and rectal delivery), pulmonary(e.g., by inhalation or insufflation of powders or aerosols, includingby nebulizer; intratracheal, intranasal, epidermal and transdermal),ocular, oral or parenteral. Methods for ocular delivery can includetopical administration (eye drops), subconjunctival, periocular orintravitreal injection or introduction by balloon catheter or ophthalmicinserts surgically placed in the conjunctival sac. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal, or intramuscular injection or infusion; orintracranial, e.g., intrathecal or intraventricular, administration.Parenteral administration can be in the form of a single bolus dose, ormay be, for example, by a continuous perfusion pump. Pharmaceuticalcompositions and formulations for topical administration may includetransdermal patches, ointments, lotions, creams, gels, drops,suppositories, sprays, liquids and powders. Conventional pharmaceuticalcarriers, aqueous, powder or oily bases, thickeners and the like may benecessary or desirable.

This disclosure also includes pharmaceutical compositions which contain,as the active ingredient, one or more compounds described herein incombination with one or more pharmaceutically acceptable carriers orexcipients. In making the compositions described herein, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders. In some embodiments, the composition issuitable for topical administration.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions described herein can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from, for example, about 5 mg to about 1000 mg, about 5 mg toabout 100 mg, about 100 mg to about 500 mg or about 10 to about 30 mg,of the active ingredient. In some embodiments, each dosage containsabout 10 mg of the active ingredient. In some embodiments, each dosagecontains about 50 mg of the active ingredient. In some embodiments, eachdosage contains about 25 mg of the active ingredient. The term “unitdosage forms” refers to physically discrete units suitable as unitarydosages for human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpre-formulation composition containing a homogeneous mixture of one ormore compounds described herein. When referring to these pre-formulationcompositions as homogeneous, the active ingredient is typicallydispersed evenly throughout the composition so that the composition canbe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid pre-formulation is thensubdivided into unit dosage forms of the type described above containingfrom, for example, 0.1 to about 500 mg of the active ingredient of thepresent disclosure.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds, or compositions as describedherein can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present disclosure can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of the compounds in a pharmaceuticalcomposition can vary depending upon a number of factors includingdosage, chemical characteristics (e.g., hydrophobicity), and the routeof administration. For example, compounds of the present disclosure canbe provided in an aqueous physiological buffer solution containing about0.1 to about 10% w/v of the compound for parenteral administration. Sometypical dose ranges are from about 1 μg/kg to about 1 g/kg of bodyweight per day. In some embodiments, the dose range is from about 0.01mg/kg to about 100 mg/kg of body weight per day. The dosage is likely todepend on such variables as the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected,formulation of the excipient, and its route of administration. Effectivedoses can be extrapolated from dose-response curves derived from invitro or animal model test systems.

Compounds described herein can also be formulated in combination withone or more additional active ingredients, which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe disclosure (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating FGFR3 protein in tissuesamples, including human, and for identifying FGFR3 ligands byinhibition binding of a labeled compound. Substitution of one or more ofthe atoms of the compounds of the present disclosure can also be usefulin generating differentiated ADME (Adsorption, Distribution, Metabolismand Excretion). Accordingly, the present invention includes FGFR bindingassays that contain such labeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹. For example, one or more hydrogenatoms in a compound of the present disclosure can be replaced bydeuterium atoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl groupof Formula (I) can be optionally substituted with deuterium atoms, suchas —CD₃ being substituted for —CH₃). In some embodiments, alkyl groupsin Formula (I) can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. In some embodiments, the compound includes twoor more deuterium atoms. In some embodiments, the compound includes 1-2,1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all of thehydrogen atoms in a compound can be replaced or substituted by deuteriumatoms.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al.J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular,substitution at one or more metabolism sites may afford one or more ofthe therapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro adenosine receptor labeling andcompetition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵, ¹³¹or ³⁵S can be useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵, ¹²³,¹²⁴, ¹³¹, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the invention can be used in a screening assay toidentify and/or evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind an FGFR3 protein by monitoring itsconcentration variation when contacting with the FGFR3, through trackingof the labeling. For example, a test compound (labeled) can be evaluatedfor its ability to reduce binding of another compound which is known tobind to a FGFR3 protein (i.e., standard compound). Accordingly, theability of a test compound to compete with the standard compound forbinding to the FGFR3 protein directly correlates to its bindingaffinity. Conversely, in some other screening assays, the standardcompound is labeled and test compounds are unlabeled. Accordingly, theconcentration of the labeled standard compound is monitored in order toevaluate the competition between the standard compound and the testcompound, and the relative binding affinity of the test compound is thusascertained.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of FGFR-associated diseases ordisorders, such as cancer and other diseases referred to herein whichinclude one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of thedisclosure. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof FGFR3 as described below.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity analysis under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm, 2.1×50 mm, Buffers: mobile phase A: 0.025% TFA in water and mobilephase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flowrate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [see“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with the 30×100 mmcolumn was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.15% NH₄OH in water and mobile phase B:acetonitrile; the flow rate was 30 mL/minute, the separating gradientwas optimized for each compound using the Compound Specific MethodOptimization protocol as described in the literature [See “PreparativeLCMS Purification: Improved Compound Specific Method Optimization”, K.Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)].Typically, the flow rate used with 30×100 mm column was 60 mL/minute.

Intermediate A.3,4-Difluoro-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Step 1. 3-Bromo-4,5-difluorobenzoic Acid

A sample of 3,4-difluorobenzoic acid (2.01 g, 12.7 mmol) was dissolvedin sulfuric acid (25 ml) and treated with NBS (2.49 g, 14.0 mmol). Thesolution was warmed to 60° C. and stirred for 16 hours. The reaction waspoured into ice water (250 mL) and diluted with EtOAc (250 mL). Thephases were separated and the aqueous portion was extracted withadditional EtOAc. The organic fractions were combined, dried withmagnesium sulfate, filtered, and concentrated in vacuo. The resultingmaterial (initially an oil, crystallizes over several days) wascollected to provide crude 3-bromo-4,5-difluorobenzoic acid (1.27 g,5.36 mmol, 42% yield). Compound does not ionize by LCMS and structurewas confirmed by subsequent steps.

Step 2. 3-Bromo-4,5-difluoro-N-methylbenzamide

A sample of 3-bromo-4,5-difluorobenzoic acid (1.27 g, 5.36 mmol) wasdissolved in DCM (26.8 ml). This solution was treated with DIPEA (1.872ml, 10.72 mmol), and HATU (2.241 g, 5.89 mmol), and stirred for 15minutes. Lastly, methylamine (8.04 ml, 2M in THF, 16.08 mmol) was addedand the mixture was stirred at 22° C. After 40 minutes, the reactionmixture was treated with saturated aqueous ammonium chloride (50 mL) anddiluted with EtOAc (100 mL). The phases were separated and the aqueousphase was extracted with additional EtOAc. The organic fractions werecombined, dried with magnesium sulfate, filtered, and concentrated invacuo. The residue was purified by flash chromatography (0-15% EtOAc inDCM) to provide 3-bromo-4,5-difluoro-N-methylbenzamide (0.403 g, 1.612mmol, 30% yield). LCMS calculated for C₈H₇BrF₂NO (M+H)⁺: m/z=250.0;found: 249.9.

Step 3.3,4-difluoro-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)

A sample of 3-bromo-4,5-difluoro-N-methylbenzamide (402 mg, 1.608 mmol)was suspended in toluene and treated with potassium acetate (316 mg,3.22 mmol) and bis(pinacolato)diboron (694 mg, 2.73 mmol). The solventwas removed in vacuo, and the residue was azeotroped twice more withtoluene. Anhydrous dioxane (16.08 ml) was added and the mixture wasstirred to dissolve. The solution was degassed by bubbling with nitrogenfor 5 mins. [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II)(131 mg, 0.161 mmol) was added and the reaction was warmed to 100° C.and stirred for 2 hours. After cooling to room temperature, the reactionwas diluted with DCM and filtered to remove the potassium acetate. Thefiltrate was concentrated in vacuo, and the residue was purified byflash chromatography (0-100% EtOAc/DCM) to afford3,4-difluoro-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(500 mg, 1.683 mmol, quant. yield). The following data is reported forthe corresponding boronic acid, which was the only observable species byLCMS. LCMS calculated for C₈H₉BF₂NO₃ (M+H)⁺: m/z=216.1; found: 216.1.

Intermediate B.4-Fluoro-N,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Step 1. 3-Bromo-4-fluoro-5-methylbenzoic Acid

A sample of 4-fluoro-3-methylbenzoic acid (2.03 g, 13.17 mmol) wasdissolved in sulfuric acid (26.3 ml) and treated with NBS (2.58 g, 14.49mmol). The solution was warmed to 60° C. and stirred for 16 hours. Thereaction was poured into ice water (500 mL) and stirred for an hour. Thesample was filtered and the solid was collected to provide crude3-bromo-4-fluoro-5-methylbenzoic acid (3.29 g, 14.12 mmol, >100%theoretical yield). Compound does not ionize by LCMS and structure wasconfirmed by subsequent steps; subsequent steps also indicate anunidentified dibrominated product.

Step 2. 3-Bromo-4-fluoro-5-formyl-N-methylbenzamide

A sample of crude 3-bromo-4-fluoro-5-methylbenzoic acid (3.29 g, 14.12mmol) was suspended in DCM (70.6 ml). This suspension was treated withDIPEA (4.93 ml, 28.2 mmol), causing complete dissolution of the startingmaterial. The solution was then treated with HATU (5.90 g, 15.53 mmol),and stirred for 15 minutes. Lastly, methylamine (21.18 ml, 2M in THF,42.4 mmol) was added and the mixture was stirred at 22° C. After 40minutes, the reaction mixture was treated with saturated aqueousammonium chloride (50 mL) and diluted with EtOAc (100 mL). The phaseswere separated and the aqueous phase was extracted with additionalEtOAc. The organic fractions were combined, dried with magnesiumsulfate, filtered, and concentrated in vacuo. The residue was purifiedby flash chromatography (0-100% EtOAc in Hexanes) to provide3-bromo-4-fluoro-N,5-dimethylbenzamide (1.4 g, 5.69 mmol, 40.3% yield).LCMS calculated for C₉H₁₀BrFNO (M+H)⁺: m/z=246.0; found: 245.9.

Step 3.4-fluoro-N,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

A sample of 3-bromo-4-fluoro-N,5-dimethylbenzamide (95 mg, 0.386 mmol)was suspended in toluene and treated with potassium acetate (114 mg,1.158 mmol) and bis(pinacolato)diboron (147 mg, 0.579 mmol). The solventwas removed in vacuo, and the residue was azeotroped twice more withtoluene. Anhydrous dioxane (3.86 ml) was added and the mixture wasstirred to dissolve. The solution was degassed by bubbling with nitrogenfor 5 minutes.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (47.3 mg,0.058 mmol) was added and the reaction was warmed to 110° C. and stirredfor 2 hours. The reaction was diluted with DCM and filtered to removesolid potassium acetate. The filtrate was concentrated in vacuo and theresidue was purified by flash column chromatography (0-100% EtOAc/DCM)to provide4-fluoro-N,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(99 mg, 0.338 mmol, 87% yield). The following data is reported for thecorresponding boronic acid, which was the only observable species byLCMS. LCMS calculated for C₉H₁₂BFNO₃ (M+H)⁺: m/z=212.1; found: 212.2.

Intermediate C.3-(Difluoromethyl)-4-fluoro-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Step 1. 3-Bromo-4-fluoro-5-formylbenzoic Acid

A sample of 4-fluoro-3-formylbenzoic acid (2.07 g, 12.31 mmol) wasdissolved in sulfuric acid (24.62 ml) and treated with NBS (2.41 g,13.54 mmol). The solution was warmed to 60° C. and stirred for 16 hours.The reaction was poured into ice water (500 mL) and stirred for an hour.The sample was filtered and the solid was collected to provide3-bromo-4-fluoro-5-formylbenzoic acid (2.63 g, 10.65 mmol, 86% yield).Compound does not ionize by LCMS and structure was confirmed bysubsequent steps.

Step 2. 3-Bromo-4-fluoro-5-formyl-N-methylbenzamide

To a solution of 3-bromo-4-fluoro-5-formylbenzoic acid (400 mg, 1.62mmol) and HATU (739 mg, 1.94 mmol) in DMF (6 ml) was added DIPEA (0.42mL, 2.43 mmol), and the reaction mixture was stirred at room temperaturefor 5 min. Methylamine (2M/THF) (1.2 mL, 2.43 mmol) was added andstirring was continued for an additional 30 min. The reaction mixturewas partitioned between water and EtOAc, and the phases were separated.The aqueous phase was extracted with EtOAc and the combined organicphases were washed with brine, dried over MgSO₄, filtered, andconcentrated. The product was purified by flash chromatography (0-100%EtOAc/hexanes) to afford the title compound (176 mg, 42%). LCMScalculated for C₉H₈BrFNO₂ (M+H)⁺: m/z=260.0; found: 260.0.

Step 3. 3-Bromo-5-(difluoromethyl)-4-fluoro-N-methylbenzamide

To a solution of 3-bromo-4-fluoro-5-formyl-N-methylbenzamide (176 mg,0.68 mmol) in DCM (4 ml) was added DAST (179 μl, 1.35 mmol) at 0° C.,and the reaction mixture was allowed to warm to room temp. After 30 min,more DAST (179 μl, 1.35 mmol) was added and stirring was continued for 1h. The reaction mixture was cooled to 0° C., carefully quenched with 5saturated aqueous NaHCO₃, and extracted with DCM. The phases wereseparated and the organic phase was washed with brine, dried over MgSO₄,filtered and concentrated. The product was purified by flashchromatography (0-100% EtOAc/hexanes). LCMS calculated for C₉H₈BrF₃NO(M+H)⁺: m/z=282.0; found: 282.0.

Step 4.3-(Difluoromethyl)-4-fluoro-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

3-Bromo-5-(difluoromethyl)-4-fluoro-N-methylbenzamide (191 mg, 0.68mmol) was combined with bis(pinacolato)diboron (430 mg, 1.69 mmol),dichloro[1,1′-bis(diphenyl-phosphino)ferrocene]palladium (II)dichloromethane adduct (27.6 mg, 0.034 mmol) and potassium acetate (199mg, 2.03 mmol) in dioxane (5 ml) and the mixture was sparged with N₂,then heated to 100° C. for 6 h. The reaction mixture was diluted withEtOAc, filtered, and concentrated. The residue was purified by flashchromatography (0-100% EtOAc/hexanes) to afford the title compound (223mg, 100%). The following data is reported for the corresponding boronicacid, which was the only observable species by LCMS. LCMS calculated forC₉H₁₀BF₃NO₃ (M+H)⁺: m/z=248.1; found: 248.1.

Intermediate D.3-Cyano-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Step 1. 3-Bromo-5-cyano-N-methylbenzamide

To a solution of 3-bromo-5-cyanobenzoic acid (500 mg, 2.21 mmol) andHATU (1.0 g, 2.65 mmol) in DMF (10 ml) was added DIPEA (580 μl, 3.32mmol), and the reaction mixture was stirred at room temp for 5 min.Methylamine (2M/THF) (1.66 mL, 3.32 mmol) was added and the reactionmixture was stirred for an additional 30 min. Ice chips and water wereadded and the mixture was stirred overnight. The resulting precipitatewas filtered, washed with water, and air dried to afford the titlecompound (263 mg, 50%). LCMS calculated for C₉H₈BrN₂O (M+H)⁺: m/z=239.0;found: 239.0.

Step 2.3-Cyano-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

This compound was synthesized by a procedure analogous to that reportedfor Intermediate C, Step 4. The following data is reported for thecorresponding boronic acid, which was the only observable species byLCMS. LCMS calculated for C₉H₁₀BN₂O₃ (M+H)⁺: m/z=205.1; found: 205.0.

Intermediate E.N-(Methyl-d₅)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide

Step 1. 5-Bromo-N-(methyl-d₃)nicotinamide

To a solution of 5-bromonicotinic acid (100 mg, 0.49 mmol) and HATU (226mg, 0.59 mmol) in DMF (4 ml) was added DIPEA (259 μl, 1.49 mmol), andthe reaction mixture was stirred at room temperature for 5 min.Methylamine-d₃ hydrochloride (41.9 mg, 0.59 mmol) was added and stirringwas continued for an additional 30 min. The reaction mixture waspartitioned between water and EtOAc, and the phases were separated. Theaqueous phase was extracted with EtOAc and the combined organic phaseswere washed with brine, dried over MgSO₄, filtered, and concentrated.The product was purified by flash chromatography (0-100% EtOAc/hexanes)to afford the title compound (94 mg, 87%) as a white solid. LCMScalculated for C₇H₅D₃BrN₂O (M+H)⁺: m/z=218.0; found: 218.0.

Step 2.N-(Methyl-d₃)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide

5-Bromo-N-(methyl-d₃)nicotinamide (94 mg, 0.43 mmol) was combined withbis(pinacolato)diboron (164 mg, 0.65 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (17.6 mg, 0.02 mmol) and potassium acetate (127mg, 1.30 mmol) in dioxane (3 ml) and the mixture was sparged with N₂ for5 min. The reaction was heated to 100° C. for 3 h. The reaction mixturewas diluted with EtOAc, filtered, and concentrated. The product was usedwithout purification, assuming quantitative yield. The following data isreported for the corresponding boronic acid, which was the onlyobservable species by LCMS. LCMS calculated for C₇H₇D₃BN₂O₃ (M+H)⁺:m/z=184.1; found: 184.2.

Intermediate F.4-Fluoro-3-methyl-N-(methyl-d₃)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Prepared by an identical procedure to that described for Intermediate B,utilizing methylamine-d₃ instead of methylamine in Step 2. The followingdata is reported for the corresponding boronic acid, which was the onlyobservable species by LCMS. LCMS calculated for C₉H₉D₃BFNO₃ (M+H)⁺:m/z=215.1; found: 215.1.

Intermediate G.3-(Difluoromethyl)-4-fluoro-N-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Prepared by an identical procedure to that described for Intermediate C,utilizing methylamine-d₃ instead of methylamine in Step 2. The followingdata is reported for the corresponding boronic acid, which was the onlyobservable species by LCMS. LCMS calculated for C₉H₇D₃BF₃NO₃ (M+H)⁺:m/z=251.1; found: 251.1.

Example 1.N-Methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide(racemic)

Step 1. 3,5,7-Trichloropyrazolo[1,5-a]pyrimidine

To a solution of 5,7-dichloropyrazolo[1,5-a]pyrimidine (500 mg, 2.66mmol, Combi-Blocks ST-4256) in DMF (5 ml) was added NCS (391 mg, 2.93mmol) and the reaction mixture was stirred at 60° C. for 1 h. Aftercooling to room temperature, ice chips and water were added. Theresulting precipitate was filtered, washed with water, and air dried toafford the title compound (460 mg, 78%) as an off-white solid. LCMScalculated for C₆H₃Cl₃N₃ (M+H)⁺: m/z=221.9; found: 221.9.

Step 2. 3,5-Dichloropyrazolo[1,5-a]pyrimidin-7-amine

A suspension of 3,5,7-trichloropyrazolo[1,5-a]pyrimidine (460 mg, 2.07mmol) in concentrated ammonium hydroxide (10 ml, 145 mmol) was heated to100° C. in a heavy walled sealed tube for 1 h. After cooling to roomtemperature, the reaction mixture was diluted with cold water andfiltered. The collected solid was then washed with cold water and airdried to afford the title compound (355 mg, 85%). LCMS calculated forC₆H₅Cl₂N₄ (M+H)⁺: m/z=203.0; found: 203.0.

Step 3. 3,5-Dichloro-6-iodopyrazolo[1,5-a]pyrimidin-7-amine

To a solution of 3,5-dichloropyrazolo[1,5-a]pyrimidin-7-amine (355 mg,1.75 mmol) in DMF (5 ml) was added NIS (590 mg, 2.62 mmol) and thereaction mixture was stirred at 50° C. for 1 h. After cooling to roomtemperature, ice chips and water were added. The resulting precipitatewas filtered, washed with water, and air dried to afford the titlecompound (489 mg, 85%). LCMS calculated for C₆H₄Cl₂IN₄ (M+H)⁺:m/z=328.9; found: 328.8.

Step 4. 3,5-Dichloro-6-iodopyrazolo[1,5-a]pyrimidine

To a solution of 3,5-dichloro-6-iodopyrazolo[1,5-a]pyrimidin-7-amine(489 mg, 1.49 mmol) in THF (4 ml) was added tert-butyl nitrite (0.88 ml,7.43 mmol), and the reaction mixture was heated to 80° C. for 2 h. Thereaction mixture was concentrated and purified by flash chromatography(0-50% EtOAc/hexanes) to afford the title compound (217 mg, 47%). LCMScalculated for C₆H₃Cl₂IN₃ (M+H)⁺: m/z=313.9; found: 313.7.

Step 5.3,5-Dichloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine

A mixture of 3,5-dichloro-6-iodopyrazolo[1,5-a]pyrimidine (217 mg, 0.69mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(158 mg, 0.760 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (28 mg, 35 μmol), andsodium carbonate (220 mg, 2.07 mmol) in dioxane (3 ml) and water (1 ml)was sparged with N₂ and heated to 80° C. for 2 h. The reaction mixturewas diluted with EtOAc and water, and filtered through celite. Thephases were separated and the organic phase was washed with brine, driedover MgSO₄, filtered and concentrated. The residue was purified by flashchromatography (0-100% EtOAc/hexanes) to afford the title compound (126mg, 68%). LCMS calculated for C₁₀H₈Cl₂N₅ (M+H)⁺: m/z=268.0; found:268.0.

Step 6.3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine(Racemic)

To a solution of3,5-dichloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (40mg, 0.15 mmol) in DMF (1 ml) was added tetrahydrofuran-3-ol (60 μl, 0.75mmol), followed by cesium carbonate (146 mg, 0.45 mmol) at roomtemperature. The reaction mixture was heated to 90° C. for 1 h. Thereaction mixture was cooled to room temperature, diluted with DMF andfiltered. The solution of the product in DMF was used directly in Step7. LCMS calculated for C₁₄H₁₅ClN₅O₂(M+H)⁺: m/z=320.1; found: 320.1.

Step 7.N-Methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide(Racemic)

A mixture of3-chloro-6-(1-methyl-H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine(10 mg, 0.03 mmol), (3-(methylcarbamoyl)phenyl)boronic acid (8.4 mg,0.05 mmol), XPhos Pd G2 (1.2 mg, 1.6 μmol), and cesium carbonate (31 mg,0.09 mmol) in DMF (1 ml) and water (0.5 ml) was sparged with N₂ andheated to 100° C. for 1 h. The reaction mixture was diluted with MeOHand filtered through a thiol siliaprep cartridge. The product waspurified by prep HPLC (pH 2). The product was isolated as the TFA salt.LCMS calculated for C₂₂H₂₃N₆O₃ (M+H)⁺: m/z=419.2; found: 419.1. ¹H NMR(500 MHz, DMSO) δ 9.32 (s, 1H), 8.61 (s, 2H), 8.44 (q, J=4.4 Hz, 1H),8.19 (s, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.50(t, J=7.7 Hz, 1H), 5.78 (td, J=4.8, 2.5 Hz, 1H), 4.19 (dd, J=10.7, 4.9Hz, 1H), 4.07 (d, J=10.6 Hz, 1H), 3.96 (q, J=7.7 Hz, 1H), 3.92 (s, 3H),3.86 (td, J=8.2, 4.7 Hz, 1H), 2.83 (d, J=4.5 Hz, 3H), 2.46 (dt, J=14.6,7.4 Hz, 1H), 2.36-2.27 (m, 1H).

Example 2.4-Fluoro-N-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide(racemic)

This compound was prepared by a procedure analogous to that describedfor Example 1, utilizing (2-fluoro-5-(methylcarbamoyl)phenyl)boronicacid instead of (3-(methylcarbamoyl)-phenyl)boronic acid in Step 7. Theproduct was isolated as the TFA salt. LCMS calculated for C₂₂H₂₁FN₆O₃(M+H)⁺: m/z=437.2; found: 437.1.

Example 3.N-Methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide(Racemic)

This compound was prepared by a procedure analogous to that describedfor Example 1, utilizing (5-(methylcarbamoyl)pyridin-3-yl)boronic acidinstead of (3-(methylcarbamoyl)-phenyl)boronic acid in Step 7. Theproduct was isolated as the TFA salt. LCMS calculated for C₂₁H₂₂N₇O₃(M+H)⁺: m/z=420.2; found: 420.1.

Example 4.4-Fluoro-N,3-dimethyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide(Racemic)

This compound was prepared by a procedure analogous to that describedfor Example 1, utilizing4-fluoro-N,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate B) instead of (3-(methylcarbamoyl)-phenyl)boronic acid inStep 7. The product was isolated as the TFA salt. LCMS calculated forC₂₃H₂₄ FN₆O₃ (M+H)⁺: m/z=451.2; found: 451.2.

Example 5.(S)-4-Fluoro-N,3-dimethyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

This compound was prepared by a procedure identical to that describedfor Example 4, utilizing (S)-tetrahydrofuran-3-ol instead of racemictetrahydrofuran-3-ol in Step 6. The product was isolated as the TFAsalt. LCMS calculated for C₂₃H₂₄ FN₆O₃ (M+H)⁺: m/z=451.2; found: 451.2.

Example 6.(S)-3-Cyano-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

Step 1. 5,6-Dichloro-3-iodopyrazolo[1,5-a]pyrimidine

This compound was prepared by a procedure analogous to that describedfor 3,5-dichloro-6-iodopyrazolo[1,5-a]pyrimidine (Example 1, Step 4),utilizing NIS instead of NCS in Step 1 and NCS instead of NIS in Step 3.LCMS calculated for C₆H₃Cl₂IN₃ (M+H)⁺: m/z=313.9; found: 313.8.

Step 2.(S)-6-Chloro-3-iodo-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine

To a solution of 5,6-dichloro-3-iodopyrazolo[1,5-a]pyrimidine (391 mg,1.25 mmol) in DMF (3.5 ml) was added (S)-tetrahydrofuran-3-ol (503 μl,6.23 mmol), followed by cesium carbonate (609 mg, 1.87 mmol) at roomtemperature. The reaction mixture was heated to 90° C. for 1 h. Aftercooling to room temperature, the reaction mixture was partitionedbetween water and EtOAc, and the phases were separated. The organicphase was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography (0-50%EtOAc/hexanes) to afford the title compound (48 mg, 11%). LCMScalculated for C₁₀H₁₀ClIN₃O₂ (M+H)⁺: m/z=366.0; found: 366.0.

Step 3.(S)-3-(6-Chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-cyanobenzoicAcid

A mixture of(S)-6-chloro-3-iodo-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine(15 mg, 0.04 mmol), methyl3-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (13 mg,0.05 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (1.7 mg, 2.1 μmol), and sodiumcarbonate (13 mg, 0.12 mmol) in dioxane (1 ml) and water (0.5 ml) wassparged with N₂ and heated to 80° C. for 2 h. The solution was thentreated with an excess of NaOH and stirred at room temperature until themethyl ester was fully hydrolyzed to the acid. The reaction mixture wasacidified to pH 1 with 1M HCl and filtered through a siliaprep thiolcartridge. The filtrate was partitioned between water and EtOAc, and thephases were separated. The aqueous phase was extracted with EtOAc andthe combined organic phases were washed with brine, dried over MgSO₄,filtered, and concentrated. The product was used without furtherpurification. LCMS calculated for C₁₈H₁₄ClN₄O₄ (M+H)⁺: m/z=385.1; found:385.1.

Step 4.(S)-3-(6-Chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-cyano-N-methylbenzamide

To a solution of(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-cyanobenzoicacid (15 mg, 0.039 mmol) and HATU (17.8 mg, 0.047 mmol) in DMF (2 ml)was added DIPEA (10 μl, 0.06 mmol), and the reaction mixture was stirredfor 5 min at room temperature. Methylamine (2M/THF) (59 μl, 0.12 mmol)was added, and the reaction mixture was stirred at room temperature foran additional 30 min. The reaction mixture was partitioned between waterand EtOAc, and the phases were separated. The aqueous phase wasextracted with EtOAc and the combined organic phases were washed withbrine, dried over MgSO₄, filtered, and concentrated. The product wasused without further purification. LCMS calculated for C₁₉H₁₇ClN₅O₃(M+H)⁺: m/z=398.1; found: 398.2.

Step 5.(S)-3-Cyano-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

A mixture of(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-cyano-N-methylbenzamide(15 mg, 0.038 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(9.4 mg, 0.045 mmol), XPhos Pd G3 (1.6 mg, 1.9 μmol), and sodiumcarbonate (12 mg, 0.11 mmol) in dioxane (1.5 ml) and water (0.5 ml) wassparged with N₂ and heated to 90° C. for 2 h. The reaction mixture wasdiluted with MeOH, filtered through a siliaprep thiol cartridge, and theproduct was purified by prep HPLC (pH 2). The product was isolated asthe TFA salt. LCMS calculated for C₂₃H₂₂N₇O₃ (M+H)⁺: m/z=444.2; found:444.2.

Example 7.(S)—N-Methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide

Step 1.(S)-3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)-N-(tetrahydrofuran-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine

To a solution of3,5-dichloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (10mg, 0.037 mmol, Example 1, Step 5) in DMF (0.5 ml) was added(S)-tetrahydrofuran-3-amine (16 mg, 0.19 mmol), followed by cesiumcarbonate (37 mg, 0.11 mmol) at room temperature. The reaction mixturewas heated to 80° C. for 1 h. After cooling to room temperature, thereaction mixture was partitioned between water and EtOAc, and the phaseswere separated. The organic phase was washed with brine, dried overMgSO₄, filtered, and concentrated. The product was used without furtherpurification. LCMS calculated for C₁₄H₁₆ClN₆O (M+H)⁺: m/z=319.1; found:319.0.

Step 2.(S)—N-Methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide

A mixture of(S)-3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-N-(tetrahydrofuran-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(10 mg, 0.031 mmol),N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide(9.9 mg, 0.038 mmol), XPhos Pd G2 (1.2 mg, 1.6 μmol), and sodiumcarbonate (10 mg, 0.094 mmol) in dioxane (1 ml) and water (0.5 ml) wassparged with N₂ and heated to 100° C. for 2 h. The reaction mixture wasdiluted with MeOH and filtered through a thiol siliaprep cartridge. Theproduct was purified by prep HPLC (pH 2). The product was isolated asthe TFA salt. LCMS calculated for C₂₁H₂₃N₈O₂ (M+H)⁺: m/z=419.2; found:419.2.

Example 8.(S)-3-Cyano-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

Step 1.(S)-3-Cyano-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzoicAcid

A mixture of(S)-3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-N-(tetrahydrofuran-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(15 mg, 0.047 mmol, Example 7, Step 1), methyl3-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (16.2mg, 0.056 mmol), XPhos Pd G2 (1.9 mg, 2.4 μmol), and sodium carbonate(15 mg, 0.14 mmol) in dioxane (1.5 ml) and water (0.5 ml) was spargedwith N₂ and heated to 100° C. for 2 h. The reaction mixture wasacidified to pH 1 with 1M HCl, diluted with EtOAc, and filtered througha thiol siliaprep cartridge. The phases were separated and the organicphase was washed with brine, dried over MgSO₄, filtered andconcentrated. The product was used without purification. LCMS calculatedfor C₂₂H₂₀N₇O₃ (M+H)⁺: m/z=430.2; found: 430.1.

Step 2.(S)-3-Cyano-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

To a mixture of(S)-3-cyano-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzoicacid (20 mg, 0.047 mmol) and HATU (21.4 mg, 0.056 mmol) in DMF (3 ml)was added DIPEA (24 μl, 0.14 mmol), and the reaction mixture was stirredat room temp for 5 min. Methylamine (2M/THF) (70 μl, 0.14 mmol) wasadded, and the reaction mixture was stirred at room temperature for anadditional 30 min. The reaction mixture was partitioned between waterand EtOAc, and the phases were separated. The organic phase was washedwith brine, dried over MgSO₄, filtered, and concentrated. The productwas purified by prep HPLC (pH 2). The product was isolated as the TFAsalt. LCMS calculated for C₂₃H₂₃N₈O₂ (M+H)⁺: m/z=443.2; found: 443.4.

Example 9.(S)-5-(6-(1-Isopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide

Step 1.3,5-Dichloro-6-(1-isopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine

A mixture of 3,5-dichloro-6-iodopyrazolo[1,5-a]pyrimidine (100 mg, 0.32mmol, Example 1, Step 4),1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(75 mg, 0.32 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (13 mg, 0.016 mmol), andsodium carbonate (101 mg, 0.96 mmol) in dioxane (2 ml) and water (0.5ml) was sparged with N₂ and heated to 80° C. for 1 h. The reactionmixture was diluted with EtOAc and water. The phases were separated andthe organic phase was washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by flash chromatography (0-100%EtOAc/hexanes) to afford the title compound (77 mg, 82%). LCMScalculated for C₁₂H₁₂Cl₂N₅ (M+H)⁺: m/z=296.0; found: 296.2.

Step 2.(S)-3-Chloro-6-(1-isopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine

To a solution of3,5-dichloro-6-(1-isopropyl-H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (10mg, 0.034 mmol) in DMF (1 ml) was added (S)-tetrahydrofuran-3-ol (14 mg,0.17 mmol), followed by cesium carbonate (16.5 mg, 0.051 mmol) at roomtemperature. The reaction mixture was heated to 80° C. for 1 h; thencooled to room temperature. The solution of the product in DMF was useddirectly for the next reaction. LCMS calculated for C₁₆H₁₉ClN₅O₂ (M+H)⁺:m/z=348.1; found: 348.1.

Step 3.(S)-5-(6-(1-Isopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide

A mixture of(S)-3-chloro-6-(1-isopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine(12 mg, 0.035 mmol),N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide(10.9 mg, 0.041 mmol), XPhos Pd G2 (1.4 mg, 1.7 μmol), and cesiumcarbonate (34 mg, 0.10 mmol) in DMF (1 ml) and water (0.5 ml) wassparged with N₂ and heated to 100° C. for 2 h. The reaction was dilutedwith MeOH, filtered through a siliaprep thiol cartridge, and the productwas purified by prep HPLC (pH 2). The product was isolated as the TFAsalt. LCMS calculated for C₂₃H₂₆N₇O₃ (M+H)⁺: m/z=448.2; found: 448.4. ¹HNMR (500 MHz, DMSO) δ 9.39 (d, J=2.1 Hz, 1H), 9.38 (s, 1H), 9.00 (t,J=2.1 Hz, 1H), 8.85 (d, J=2.0 Hz, 1H), 8.74 (s, 1H), 8.72 (q, J=4.9, 4.4Hz, 1H), 8.28 (s, 1H), 8.06 (s, 1H), 5.79 (td, J=4.7, 2.4 Hz, 1H), 4.58(p, J=6.7 Hz, 1H), 4.17 (dd, J=10.7, 4.7 Hz, 1H), 4.11-4.05 (m, 1H),3.96 (q, J=8.1 Hz, 1H), 3.88 (td, J=8.3, 4.7 Hz, 1H), 2.86 (d, J=4.5 Hz,3H), 2.46 (dt, J=14.6, 7.3 Hz, 1H), 2.36-2.26 (m, 1H), 1.47 (d, J=6.6Hz, 6H).

Example 10.(S)-5-(6-(1-Isopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide

Step 1.(S)-3-Chloro-6-(1-Isopropyl-1H-pyrazol-4-yl)-N-(tetrahydrofuran-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine

To a solution of3,5-dichloro-6-(1-isopropyl-H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (10mg, 0.034 mmol, Example 9, Step 1) in DMF (1 ml) was added(S)-tetrahydrofuran-3-amine (15 mg, 0.17 mmol), followed by cesiumcarbonate (16.5 mg, 0.051 mmol) at room temperature. The reactionmixture was heated to 80° C. for 1 h, then cooled to room temperature.The reaction mixture was partitioned between water and EtOAc, and thephases were separated. The organic phase was washed with brine, driedover MgSO₄, filtered, and concentrated. The residue was used withoutpurification. LCMS calculated for C₁₆H₂₀ClN₆O (M+H)⁺: m/z=347.1; found:347.2.

Step 2.(S)-5-(6-(1-Isopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide

This compound was synthesized by a procedure analogous to that describedin Example 9, Step 3. The product was isolated as the TFA salt. LCMScalculated for C₂₃H₂₇NO₂ (M+H)⁺: m/z=447.2; found: 447.4.

Example 11.(S)-3,4-Difluoro-N-methyl-5-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

Step 1. 3-Bromo-5,6-dichloropyrazolo[1,5-a]pyrimidine

This compound was prepared by a procedure analogous to that describedfor 3,5-dichloro-6-iodopyrazolo[1,5-a]pyrimidine (Example 1, Step 4),utilizing NBS instead of NCS in Step 1 and NCS instead of NIS in Step 3.LCMS calculated for C₆H₃BrCl₂N₃ (M+H)⁺: m/z=265.9; found: 265.9.

Step 2.(S)-3-Bromo-6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine

A mixture of 3-bromo-5,6-dichloropyrazolo[1,5-a]pyrimidine (340 mg, 1.27mmol), (S)-tetrahydrofuran-3-ol (515 μl, 6.37 mmol), and cesiumcarbonate (623 mg, 1.91 mmol) in THF (6 ml) was heated to 80° C. for 2h. The reaction mixture was cooled to room temperature, diluted withEtOAc, and filtered. The filtrate was concentrated in vacuo and theresidue was purified by flash chromatography (0-50% EtOAc/hexanes) toafford the title compound (271 mg, 67%) as a light yellow solid. LCMScalculated for C₁₀H₁₀BrClN₃O₂ (M+H)⁺: m/z=318.0; found: 317.9.

Step 3.(S)-3-(6-Chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-4,5-difluoro-N-methylbenzamide

A mixture of(S)-3-bromo-6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine(30 mg, 0.094 mmol),3,4-difluoro-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(33 mg, 0.11 mmol, Intermediate A), PdCl₂(dppf)-CH₂Cl₂ adduct (7.7 mg,9.4 μmol), and sodium carbonate (30 mg, 0.28 mmol) in dioxane (1.5 ml)and water (0.5 ml) was sparged with N₂ and heated to 100° C. for 2 h.More3,4-difluoro-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(33 mg, 0.11 mmol, Intermediate A) was added and heating was continuedfor an additional 1 h. The reaction mixture was diluted with EtOAc andfiltered through a siliaprep thiol cartridge. The filtrate waspartitioned between water and EtOAc, and the phases were separated. Theaqueous phase was extracted with EtOAc and the combined organic phaseswere washed with brine, dried over MgSO₄, filtered, and concentrated.The residue was purified by flash chromatography (0-100% EtOAc/hexanes)to afford the title compound. LCMS calculated for C₁₈H₁₆ClF₂N₄O₃ (M+H)⁺:m/z=409.1; found: 409.2.

Step 4.(S)-3,4-Difluoro-N-methyl-5-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

A mixture of(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-4,5-difluoro-N-methylbenzamide(10 mg, 0.02 mmol),1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine(6 mg, 0.02 mmol), XPhos Pd G2 (1.9 mg, 2.5 μmol), and cesium carbonate(24 mg, 0.073 mmol) in dioxane (1 ml) and water (0.5 ml) was spargedwith N₂ and heated to 100° C. for 2 h. The reaction mixture was dilutedwith MeOH and filtered through a thiol siliaprep cartridge. The productwas purified by prep HPLC (pH 2). The product was isolated as the TFAsalt. LCMS calculated for C₂₇H₃₀F₂N₇O₃ (M+H)⁺: m/z=538.2; found: 538.3.

Examples 12-15

The compounds in the following table were synthesized according to theprocedure described for Example 11, utilizing the appropriatecommercially available boronate or boronic acid in Step 4. The productswere isolated as TFA salts.

Example No. and Compound Name Cy¹ LCMS 12. (S)-3,4-Difluoro-N-methy1-5-(6-(4-(4- methylpiperazin-1- yl)pheny1)-5- ((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

LCMS calculated for C₂₉H₃₁F₂N₆O₃ (M + H)⁺: m/z = 549.2; found: 549.3.13. (S)-3,4-Difluoro-N- methy1-5-(6-(6-(4- methylpiperazin-1-yl)pyridin-3-y1)-5- ((tetrahydrofuran-3- yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

LCMS calculated for C₂₈H₃₀F₂N₇O₃ (M + H)⁺: m/z = 550.2; found: 550.3.14. (S)-3,4-Difluoro-N- methy1-5-(6-(1-(2- morpholinoethyl)-1H-pyrazol-4-y1)-5- ((tetrahydrofuran-3- yl)oxy)pyrazolo[1,5-

LCMS calculated for C₂₇H₃₀F₂N₇O₄ (M + H)⁺: m/z = 554.2; found: 554.3.a]pyrimidin-3-yl)benzamide 15. (S)-3,4-Difluoro-N- methyl-5-(6-(6-methylpyridin-3-y1)-5- ((tetrahydrofuran-3- yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

LCMS calculated for C₂₄H₂₂F₂N₅O₃ (M + H)⁺: m/z = 466.2; found: 466.2.

Example 16.(S)-4-Fluoro-N,3-dimethyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

Step 1.(S)-4-Fluoro-3-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzoicAcid

A mixture of(S)-3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-N-(tetrahydrofuran-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(15 mg, 0.047 mmol, Example 7, Step 1),4-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid (15.8 mg, 0.056 mmol, Combi-Blocks), XPhos Pd G2 (1.9 mg, 2.4μmol), and sodium carbonate (15 mg, 0.14 mmol) in dioxane (1.5 ml) andwater (0.5 ml) was sparged with N₂ and heated to 100° C. for 2 h. Thereaction mixture was diluted with MeOH, filtered through a siliaprepthiol cartridge, and the product was purified by prep HPLC (pH 2) toafford the title compound (5 mg, 24%). LCMS calculated for C₂₂H₂₂FN₆O₃(M+H)⁺: m/z=437.2; found: 437.2.

Step 2.(S)-4-Fluoro-N,3-dimethyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

To a mixture of(S)-4-fluoro-3-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzoicacid (5 mg, 0.011 mmol) and HATU (8.7 mg, 0.023 mmol) in DMF (2 ml) wasadded DIPEA (6 μl, 0.03 mmol), and the reaction mixture was stirred atroom temp for 5 min. Methylamine (2M/THF) (17 μl, 0.034 mmol) was addedand the reaction mixture was stirred for an additional 30 min. Thereaction mixture was diluted with methanol and the product was purifiedby prep HPLC (pH 2). The product was isolated as the TFA salt. LCMScalculated for C₂₃H₂₅FN₇O₂ (M+H)⁺: m/z=450.2; found: 450.2.

Example 17.(S)-3,4-Difluoro-N-methyl-5-(6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

Step 1.tert-Butyl(S)-3-(4-(3-(2,3-difluoro-5-(methylcarbamoyl)phenyl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

A mixture of(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-4,5-difluoro-N-methylbenzamide(10 mg, 0.024 mmol, Example 11, Step 3), tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(10.3 mg, 0.029 mmol), XPhos Pd G2 (1.9 mg, 2.5 μmol), and cesiumcarbonate (24 mg, 0.073 mmol) in dioxane (1 ml) and water (0.5 ml) wassparged with N₂ and heated to 100° C. for 2 h. The reaction was dilutedwith MeOH and filtered through a thiol siliaprep cartridge. The filtratewas concentrated and the residue was used without further purification.LCMS calculated for C₂₉H₃₂F₂N₇O₅ (M+H)⁺: m/z=596.2; found: 596.4.

Step 2.(S)-3,4-Difluoro-N-methyl-5-(6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

To a solution of tert-butyl(S)-3-(4-(3-(2,3-difluoro-5-(methylcarbamoyl)phenyl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(15 mg, 0.025 mmol) in DCM (1.5 ml) was added TFA (0.5 ml, 6.5 mmol) andthe reaction mixture was stirred at room temp for 30 min. The reactionmixture was concentrated, dissolved in MeOH (2 ml), and treatedsequentially with formaldehyde (0.094 ml, 1.26 mmol) and sodiumcyanoborohydride (7.9 mg, 0.126 mmol). After stirring for 3 h, thereaction mixture was diluted with MeOH and purified by prep HPLC (pH 2).The product was isolated as the TFA salt. LCMS calculated forC₂₅H₂₆F₂N₇O₃ (M+H)⁺: m/z=510.2; found: 510.5.

Example 18.(S)—N-Methyl-5-(6-(4-(4-methylpiperazin-1-yl)phenyl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide

Step 1.(S)-5-(6-Chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide

A mixture of(S)-3-bromo-6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine(60 mg, 0.19 mmol, Example 11, Step 2),N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (59mg, 0.23 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (7.7 mg, 9.4 μmol), and sodiumcarbonate (60 mg, 0.57 mmol) in dioxane (1.5 ml) and water (0.5 ml) wassparged with N₂ and heated to 100° C. for 2 h. The reaction mixture wasdiluted with EtOAc and filtered through a siliaprep thiol cartridge. Thefiltrate was washed with water and brine, and the phases were separated.The organic phase was dried over MgSO₄, filtered, and concentrated. Theresidue was used without further purification. LCMS calculated forC₁₇H₁₇ClN₅O₃ (M+H)⁺: m/z=374.1; found: 374.1.

Step 2.(S)—N-Methyl-5-(6-(4-(4-methylpiperazin-1-yl)phenyl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide

A mixture of(S)-5-(6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide(10 mg, 0.027 mmol),1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine(12 mg, 0.04 mmol), XPhos Pd G2 (2.1 mg, 2.7 μmol), and cesium carbonate(26 mg, 0.08 mmol) in dioxane (1 ml) and water (0.5 ml) was sparged withN₂ and heated to 100° C. for 2 h. The reaction mixture was diluted withMeOH and filtered through a thiol siliaprep cartridge. The product waspurified by prep HPLC (pH 2). The product was isolated as the TFA salt.LCMS calculated for C₂₈H₃₁N₇O₃ (M+H)⁺: m/z=514.3; found: 514.2.

Examples 19-22

The compounds in the following table were synthesized according to theprocedure described for Example 18, utilizing the appropriatecommercially available boronate or boronic acid in Step 2. The productswere isolated as TFA salts.

Example No. Cy¹ LCMS 19. (S)-N-Methyl-5-(6-(6-(4- methylpiperazin-1-yl)pyridin-3-yl)-5- ((tetrahydrofuran-3- yl)oxy)pyrazolo[1,5-a]pyrimidin-3- yl)nicotinamide

LCMS calculated for C₂₇H₃₁N₈O₃ (M + H)⁺: m/z = 515.2; found: 515.2. 20.(S)-N-Methyl-5-(6-(6- morpholinopyridin-3-yl)-5- ((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5- a]pyrimidin-3- yl)nicotinamide

LCMS calculated for C₂₆H₂₈N₇O₄ (M + H)⁺: m/z = 502.2; found: 502.2.21.(S)-5-(6-(1-Cyclopropyl- 1H-pyrazol-4-yl)-5- ((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5- a]pyrimidin-3-yl)-N- methylnicotinamide

LCMS calculated for C₂₃H₂₄N₇O₃ (M + H)⁺: m/z = 446.2; found: 446.3. 22.(S)-5-(6-(1-Cyclobutyl- 1H-pyrazol-4-yl)-5- ((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5- a]pyrimidin-3-yl)-N- methylnicotinamide

LCMS calculated for C₂₄H₂₆N₇O₃ (M + H)⁺: m/z = 460.2; found: 460.3.

Example 23.(S)-3-(Difluoromethyl)-4-fluoro-N-methyl-5-(6-(pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

Step 1.(S)-3-(6-Chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-(difluoromethyl)-4-fluoro-N-methylbenzamide

A mixture of(S)-3-bromo-6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine(50 mg, 0.16 mmol),3-(difluoromethyl)-4-fluoro-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(46.5 mg, 0.19 mmol, Intermediate C), PdCl₂(dppf)-CH₂Cl₂ adduct (6.4 mg,7.9 μmol), and sodium carbonate (50 mg, 0.47 mmol) in dioxane (1 ml) andwater (0.5 ml) was thoroughly deoxygenated by two freeze-pump-thawcycles, and heated to 100° C. for 2 h. The reaction mixture was dilutedwith EtOAc and filtered through a siliaprep thiol cartridge. Thefiltrate was concentrated and the residue was purified by flashchromatography (0-100% EtOAc/hexanes) to afford the title compound (41mg, 59%), which was contaminated with ˜30% of protodeborylatedby-product. LCMS calculated for C₁₉H₁₇CF₃N₄O₃ (M+H)⁺: m/z=441.1; found:441.1.

Step 2.(S)-3-(Difluoromethyl)-4-fluoro-N-methyl-5-(6-(pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

A mixture of(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-(difluoromethyl)-4-fluoro-N-methylbenzamide(10 mg, 0.023 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (9.3 mg, 0.045mmol), XPhos Pd G2 (1.8 mg, 2.3 μmol), and cesium carbonate (22 mg,0.068 mmol) in dioxane (1.5 ml) and water (0.5 ml) was sparged with N₂and heated to 100° C. for 2 h. The reaction mixture was diluted withMeOH and filtered through a thiol siliaprep cartridge. The product waspurified by prep HPLC (pH 2). The product was isolated as the TFA salt.LCMS calculated for C₂₄H₂₁F₃N₅O₃ (M+H)⁺: m/z=484.2; found: 484.2.

Example 24.(S)-3-(Difluoromethyl)-4-fluoro-N-methyl-5-(6-(5-methyl-6-(methylamino)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

This compound was synthesized by a procedure analogous to that describedfor Example 23, utilizingN,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amineinstead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine inStep 2. The product was isolated as the TFA salt. LCMS calculated forC₂₆H₂₆F₃N₆O₃ (M+H)⁺: m/z=527.2; found: 527.3.

Example 25.(S)-3-(Difluoromethyl)-4-fluoro-5-(6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylbenzamide

This compound was synthesized by a procedure analogous to that describedfor Example 23, utilizing2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propan-2-olinstead of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine inStep 2. The product was isolated as the TFA salt. LCMS calculated forC₂₇H₂₇F₃N₅O₄ (M+H)⁺: m/z=542.2; found: 542.2.

Example 26.(S)-3-(Difluoromethyl)-4-fluoro-N-methyl-5-(6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

This compound was synthesized by a procedure analogous to that describedfor Example 17, utilizing(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-(difluoromethyl)-4-fluoro-N-methylbenzamideinstead of(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-4,5-difluoro-N-methylbenzamidein Step 1. The product was isolated as the TFA salt. LCMS calculated forC₂₆H₂₇F₃N₇O₃ (M+H)⁺: m/z=542.2; found: 542.3.

Example 27.(S)-3-Cyano-N-methyl-5-(6-(pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

Step 1.(S)-3-(6-Chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-cyano-N-methylbenzamide

A mixture of(S)-3-bromo-6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine(50 mg, 0.16 mmol, Example 11, Step 2),3-cyano-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(64 mg, 0.31 mmol, Intermediate D), PdCl₂(dppf)-CH₂Cl₂ adduct (6.4 mg,7.9 μmol), and sodium carbonate (50 mg, 0.47 mmol) in dioxane (2 ml) andwater (0.5 ml) was sparged with N₂ and heated to 100° C. for 2 h. Thereaction mixture was diluted with EtOAc and filtered through a siliaprepthiol cartridge. The filtrate was concentrated and the residue was usedwithout purification. LCMS calculated for C₁₉H₁₇ClN₅O₃ (M+H)⁺:m/z=398.1; found: 398.1.

Step 2.(S)-3-Cyano-N-methyl-5-(6-(pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

A mixture of(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-cyano-N-methylbenzamide(15 mg, 0.038 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (23.2 mg, 0.11mmol), XPhos Pd G2 (1.5 mg, 1.9 μmol), and cesium 20 carbonate (37 mg,0.11 mmol) in DMF (1.5 ml) and Water (0.5 ml) was sparged with N₂ andheated to 100° C. for 2 h. The reaction mixture was diluted with MeOHand filtered through a thiol siliaprep cartridge. The product waspurified by prep HPLC (pH 2). The product was isolated as the TFA salt.LCMS calculated for C₂₄H₂₁N₆O₃ (M+H)⁺: m/z=441.2; found: 441.2.

Examples 28-30

The compounds in the following table were synthesized according to theprocedure described for Example 27, utilizing the appropriatecommercially available boronate or boronic acid in Step 2. The productswere isolated as TFA salts.

Example No. Cy¹ LCMS 28. (S)-3-Cyano-N-methyl-5-(6-(6-methylpyridin-3-yl)- 5-((tetrahydrofuran-3- yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

LCMS calculated for C₂₅H₂₂N₆O₃ (M + H)⁺: m/z = 455.2; found: 455.2. 29.(S)-3-Cyano-N-methyl- 5-(6-(5-methylpyridin-3-yl)-5-((tetrahydrofuran-3- yl)oxy)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

LCMS calculated for C₂₅H₂₂N₆O₃ (M + H)⁺: m/z = 455.2; found: 455.3. 30.(S)-3-Cyano-N-methyl- 5-(6-(pyridin-4-yl)-5- ((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

LCMS calculated for C₂₄H₂₁N₆O₃ (M + H)⁺: m/z = 441.2; found: 441.2.

Example 31.(S)-4-Fluoro-3-hydroxy-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

Step 1. 3-Bromo-4-fluoro-5-iodobenzoic Acid

To a mixture of 3-bromo-4-fluorobenzoic acid (500 mg, 2.28 mmol) insulfuric acid (5 mL, 94 mmol) at 0° C. was added NIS (514 mg, 2.28 mmol)and the reaction mixture was allowed to warm to room temperature. Afterstirring for 1 h, a thick precipitate formed and stirring became verydifficult. At this point, the reaction was quenched with ice water andthe precipitate was filtered. The solid was washed with water, saturatedNaS₂O₃, and air dried. LCMS indicated one peak but the product did notionize. The LCMS was compared to an LCMS of the starting material andthe change in retention time was consistent with the desired product.

Step 2. 3-Bromo-4-fluoro-5-hydroxybenzoic Acid

A mixture of 3-bromo-4-fluoro-5-iodobenzoic acid (739 mg, 2.14 mmol),copper(I) oxide (36.8 mg, 0.26 mmol), and sodium hydroxide (428 mg, 10.7mmol) in water (10 ml) was heated to 100° C. overnight. LCMS indicatedseveral products, all of which did not ionize and could not beidentified by mass. After cooling to room temperature, the reactionmixture was adjusted to pH 1 with 6M HCl and the aqueous solution wasextracted with EtOAc three times. The organic phase was washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue wasused without further purification.

Step 3. 3-Bromo-4-fluoro-5-hydroxy-N-methylbenzamide

To a solution of 3-bromo-4-fluoro-5-hydroxybenzoic acid (500 mg, 2.13mmol) and HATU (809 mg, 2.13 mmol) in DMF (10 ml) was added DIPEA (0.82mL, 4.68 mmol), and the reaction mixture was stirred at room temperaturefor 5 min. Methylamine (2M/THF) (1.60 mL, 3.19 mmol) was added andstirring was continued for an additional 30 min. The reaction mixturewas partitioned between water and EtOAc, and the phases were separated.The aqueous phase was extracted with EtOAc and the combined organicphases were washed with brine, dried over MgSO₄, filtered, andconcentrated. The product was purified by flash chromatography (0-100%EtOAc/hexanes) followed by 0-20% MeOH/DCM to afford the title compound(164 mg, 31%, yield over 2 steps). LCMS calculated for C₈H₈BrFNO₂(M+H)⁺:m/z=248.0; found: 248.0.

Step 4. 3-Bromo-4-fluoro-5-((4-methoxybenzyl)oxy)-N-methylbenzamide

To a solution of 3-bromo-4-fluoro-5-hydroxy-N-methylbenzamide (40 mg,0.16 mmol) in DMF (1 ml) was added potassium carbonate (33 mg, 0.24mmol) and 1-(chloromethyl)-4-methoxybenzene (22 μl, 0.16 mmol), and thereaction mixture was heated to reflux for 2 h. The reaction mixture waspartitioned between water and EtOAc, and the phases were separated. Theaqueous phase was extracted with EtOAc and the combined organic phaseswere washed with brine, dried over MgSO₄, filtered, and concentrated.The product was purified by flash chromatography (0-70% EtOAc/hexanes)to afford the title compound (41 mg, 69%). LCMS calculated forC₁₆H₁₆BrFNO₃ (M+H)⁺: m/z=368.0; found: 368.0.

Step 5.4-Fluoro-3-((4-methoxybenzyl)oxy)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

3-Bromo-4-fluoro-5-((4-methoxybenzyl)oxy)-N-methylbenzamide (41 mg, 0.11mmol) was combined with bis(pinacolato)diboron (71 mg, 0.28 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (4.5 mg, 5.5 μmol) and potassium acetate (33 mg,0.33 mmol) in dioxane (1.5 ml) and the mixture was sparged with N₂. Thereaction was heated to 100° C. for 4 h. The reaction mixture was dilutedwith EtOAc, filtered through a siliaprep thiol cartridge, andconcentrated. The product was used without further purification. Thefollowing data is reported for the corresponding boronic acid, which wasthe only observable species by LCMS. LCMS calculated for C₁₆H₁₈BFNO₅(M+H)⁺: m/z=334.1; found: 334.2.

Step 6.(S)-3-(6-Chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-5-((4-methoxybenzyl)oxy)-N-methylbenzamide

A mixture of(S)-3-bromo-6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine(30 mg, 0.094 mmol),(2-fluoro-3-((4-methoxybenzyl)oxy)-5-(methylcarbamoyl)phenyl)boronicacid (38 mg, 0.11 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (3.9 mg, 4.7 μmol),and sodium carbonate (30 mg, 0.29 mmol) in dioxane (1 ml) and water (0.5ml) was sparged with N₂ and heated to 100° C. for 2 h. The reactionmixture was diluted with EtOAc and filtered through a siliaprep thiolcartridge. The filtrate was concentrated and the residue was usedwithout further purification. LCMS calculated for C₂₆H₂₅ClFN₄O₅ (M+H)⁺:m/z=527.1; found: 527.1.

Step 7.(S)-4-Fluoro-3-hydroxy-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

A mixture of(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-5-hydroxy-N-methylbenzamide(10 mg, 0.025 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(7.7 mg, 0.037 mmol), XPhos Pd G2 (1.0 mg, 1.2 μmol), and cesiumcarbonate (24 mg, 0.07 mmol) in dioxane (1 ml) and water (0.5 ml) wassparged with N₂ and heated to 100° C. for 2 h. The reaction mixture wasdiluted with MeOH and filtered through a thiol siliaprep cartridge andthe filtrate was concentrated.

The residue was dissolved in DCM (3 mL) and treated with TFA (0.5 mL).After stirring for 30 min at room temperature, the reaction mixture wasconcentrated. The residue was dissolved in MeOH and purified by prepHPLC (pH 2). The product was isolated as the TFA salt. LCMS calculatedfor C₂₂H₂₂FN₆O₄ (M+H)⁺: m/z=453.2; found: 453.2.

Example 32.(S)-3-(6-(1-Cyclobutyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methyl-5-(methylsulfonyl)benzamide

Step 1. 3-Bromo-N-methyl-5-(methylsulfonyl)benzamide

To a solution of 3-bromo-5-(methylsulfonyl)benzoic acid (200 mg, 0.72mmol) and HATU (327 mg, 0.86 mmol) in DMF (5 ml) was added DIPEA (0.19mL, 1.08 mmol), and the reaction mixture was stirred at room temperaturefor 5 min. Methylamine (2M/THF) (0.54 mL, 1.08 mmol) was added and thereaction mixture was stirred for an additional 30 min. The reactionmixture was partitioned between water and EtOAc, and the phases wereseparated. The aqueous phase was extracted with EtOAc and the combinedorganic phases were washed with brine, dried over MgSO₄, filtered, andconcentrated. The product was purified by flash chromatography (0-100%EtOAc/hexanes). LCMS calculated for C₉H₁₁BrNO₃S (M+H)⁺: m/z=292.0;found: 291.9.

Step 2.N-Methyl-3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

3-Bromo-N-methyl-5-(methylsulfonyl)benzamide (209 mg, 0.72 mmol) wascombined with bis(pinacolato)diboron (273 mg, 1.07 mmol),dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium (II)dichloromethane adduct (29.2 mg, 0.036 mmol) and potassium acetate (211mg, 2.15 mmol) in dioxane (5 ml) and the mixture was sparged with N₂.The reaction was heated to 100° C. for 3 h. The reaction mixture wasdiluted with EtOAc, filtered, and concentrated. The product was purifiedby flash chromatography (0-100% EtOAc/hexanes) to afford the titlecompound (236 mg, 97%). The following data is reported for thecorresponding boronic acid, which was the only observable species byLCMS. LCMS calculated for C₉H₁₃BNO₅S (M+H)⁺: m/z=258.1; found: 258.1.

Step 3.(S)-3-(6-Chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methyl-5-(methylsulfonyl)benzamide

A mixture of(S)-3-bromo-6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine(37 mg, 0.12 mmol),N-methyl-3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(47.3 mg, 0.14 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (4.7 mg, 5.8 μmol), andsodium carbonate (37 mg, 0.35 mmol) in dioxane (1 ml) and water (0.5 ml)was sparged with N₂ and heated to 100° C. for 2 h. The reaction mixturewas diluted with EtOAc and filtered through a siliaprep thiol cartridge.The filtrate was concentrated and the residue was used without furtherpurification. LCMS calculated for C₁₉H₂₀ClN₄O₅S (M+H)⁺: m/z=451.1;found: 451.1.

Step 4.(S)-3-(6-(1-Cyclobutyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methyl-5-(methylsulfonyl)benzamide

A mixture of(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methyl-5-(methylsulfonyl)benzamide(10 mg, 0.022 mmol),1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(11 mg, 0.04 mmol), XPhos Pd G2 (0.9 mg, 1.1 μmol), and cesium carbonate(22 mg, 0.07 mmol) in DMF (1.5 ml) and water (0.5 ml) was sparged withN₂ and heated to 100° C. for 2 h. The reaction mixture was diluted withMeOH and filtered through a thiol siliaprep cartridge. The product waspurified by prep HPLC (pH 2). The product was isolated as the TFA salt.LCMS calculated for C₂₆H₂₉N₆O₅S (M+H)⁺: m/z=537.2; found: 537.2.

Example 33.(S)-3-(1H-Indazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine

Step 1.(S)-6-Chloro-3-(1H-indazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine

A mixture of(S)-3-bromo-6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine(10 mg, 0.03 mmol, Example 11, Step 2),(1-(tert-butoxycarbonyl)-1H-indazol-4-yl)boronic acid (9.9 mg, 0.04mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (1.3 mg, 1.6 μmol), and potassiumphosphate, dibasic (16.4 mg, 0.10 mmol) in dioxane (1 ml) and water (0.5ml) was sparged with N₂ and heated to 100° C. for 2 h. The reactionmixture was diluted with EtOAc and filtered through a siliaprep thiolcartridge. The filtrate was concentrated and the residue was usedwithout purification. LCMS calculated for C₁₇H₁₅ClN₅O₂(M+H)⁺: m/z=356.1;found: 356.1.

Step 2.(S)-3-(1H-Indazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine

A mixture of(S)-6-chloro-3-(1H-indazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine(10 mg, 0.03 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(8.8 mg, 0.04 mmol), XPhos Pd G2 (1.1 mg, 1.4 μmol), and cesiumcarbonate (27.5 mg, 0.08 mmol) in dioxane (3 ml) and water (0.5 ml) wassparged with N₂ and heated to 100° C. for 2 h. The reaction was dilutedwith MeOH and filtered through a thiol siliaprep cartridge. The productwas purified by prep HPLC (pH 2). LCMS calculated for C₂₁H₂₀N₇O₂ (M+H)⁺:m/z=402.2; found: 402.2.

Example 34.(S)-4-Fluoro-N,3-dimethyl-5-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

Step 1.(S)-3-Bromo-6-chloro-N-(tetrahydrofuran-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine

A mixture of 3-bromo-5,6-dichloropyrazolo[1,5-a]pyrimidine (500 mg, 1.87mmol, Example 11, Step 1), (S)-tetrahydrofuran-3-amine (485 μl, 5.62mmol), and cesium carbonate (732 mg, 2.25 mmol) in THE (6 ml) was heatedto 80° C. for 2 h. The reaction mixture was cooled to room temperature,diluted with EtOAc, and filtered. The filtrate was concentrated in vacuoand the residue was purified by flash chromatography (0-50%EtOAc/hexanes) to afford the title compound (414 mg, 70%) as a lightyellow solid. LCMS calculated for C₁₀H₁₁BrClN₄O (M+H)⁺: m/z=317.0;found: 316.8.

Step 2.(S)-3-(6-Chloro-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-N,5-dimethylbenzamide

A mixture of(S)-3-bromo-6-chloro-N-(tetrahydrofuran-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(97.5 mg, 0.31 mmol, Example 34, Step 1),4-fluoro-N,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(135 mg, 0.46 mmol, Intermediate B),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(21.7 mg, 0.03 mmol), and cesium fluoride (140 mg, 0.92 mmol) in n-BuOH(2.5 ml) and water (0.5 ml) was sparged with N₂ and heated to 70° C. for1 h. The reaction mixture was cooled to room temperature and dry loadedonto silica gel. The product was purified by flash chromatography(0-100% EtOAc/hexanes followed by 0-15% MeOH/DCM) to afford the titlecompound (86 mg, 69%). LCMS calculated for C₁₉H₂₀ClFN₅O₂ (M+H)⁺:m/z=404.1; found: 404.2.

Step 3.tert-Butyl(S)-4-(4-(3-(2-fluoro-3-methyl-5-(methylcarbamoyl)phenyl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A mixture of(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-N,5-dimethylbenzamide(10 mg, 0.03 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(14 mg, 0.04 mmol), XPhos Pd G2 (0.9 mg, 1.3 μmol), and cesium carbonate(24 mg, 0.07 mmol) in dioxane (1 ml) and water (0.5 ml) was sparged withN₂ and heated to 100° C. for 2 h. The reaction mixture was diluted withMeOH and filtered through a thiol siliaprep cartridge. The filtrate wasconcentrated and the product was used without purification. LCMScalculated for C₃₂H₄₀FN₈O₄ (M+H)⁺: m/z=619.3; found: 619.4.

Step 4.(S)-4-Fluoro-N,3-dimethyl-5-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

To a solution of tert-butyl(S)-4-(4-(3-(2-fluoro-3-methyl-5-(methylcarbamoyl)phenyl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(14 mg, 0.02 mmol) in DCM (1.5 ml) was added HCl (4M/dioxane, 2 mL, 8.0mmol) and the reaction mixture was stirred at room temperature for 30min. The reaction mixture was triturated with EtOAc, redissolved in MeOH(2 ml), and treated sequentially with formaldehyde (84 μL, 1.1 mmol) andsodium cyanoborohydride (7.1 mg, 0.1 mmol). After stirring for 2 h, thereaction mixture was diluted with MeOH and purified by prep HPLC. LCMScalculated for C₂₈H₃₄FN₈O₂ (M+H)⁺: m/z=533.3; found: 533.3. ¹H NMR (500MHz, DMSO-d₆) δ 9.58 (s, 1H), 8.99 (dd, J=7.2, 2.3 Hz, 1H), 8.68 (s,1H), 8.35-8.30 (m, 1H), 8.29 (d, J=3.8 Hz, 1H), 8.18 (s, 1H), 7.87 (s,1H), 7.53 (dd, J=6.7, 2.3 Hz, 1H), 6.66 (d, J=5.6 Hz, 1H), 4.73-4.65 (m,1H), 4.52 (tt, J=11.8, 4.1 Hz, 1H), 4.12 (dd, J=9.1, 6.5 Hz, 1H), 3.87(q, J=7.6 Hz, 1H), 3.79-3.71 (m, 2H), 3.61 (d, J=12.3 Hz, 2H), 3.25-3.14(m, 2H), 2.87-2.83 (m, 2H), 2.78 (d, J=4.5 Hz, 2H), 2.43-2.35 (m, 2H),2.34 (s, 3H), 2.28-2.12 (m, 2H), 2.07-1.99 (m, 1H).

Example 35.(S)-4-Fluoro-N,3-dimethyl-5-(6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

This compound was prepared by a procedure identical to that describedfor(S)-4-fluoro-N,3-dimethyl-5-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide(Example 33), utilizing tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylateinstead of tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylatein Step 3. LCMS calculated for C₂₆H₃₀FN₈O₂ (M+H)⁺: m/z=505.2; found:505.3.

Example 36.(S)-4-Fluoro-3-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,5-dimethylbenzamide

A mixtureof(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-N,5-dimethylbenzamide(10 mg, 0.03 mmol, Example 34, Step 2),2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol(8.8 mg, 0.04 mmol), XPhos Pd G2 (1.0 mg, 1.2 μmol), and cesiumcarbonate (24 mg, 0.07 mmol) in dioxane (1 ml) and water (0.5 ml) wassparged with N₂ and heated to 100° C. for 2 h. The reaction mixture wasdiluted with MeOH and filtered through a thiol siliaprep cartridge. Theproduct was purified by prep HPLC (pH 2). LCMS calculated forC₂₄H₂₇FN₇O₃ (M+H)⁺: m/z=480.2; found: 480.2.

Examples 37-44

The compounds in the following table were prepared by a procedureanalogous to that described for Example 36, utilizing the appropriatecommercially available boronate.

Example No. R LCMS 37. (S)-3-(6-(1-(2- Cyanoethyl)-1H-pyrazol-4-y1)-5-((tetrahydrofuran-3- yl)amino)pyrazolo[1,5-a]pyrimidin-3-y1)-4-fluoro- N,5-dimethylbenzamide

Calculated for C₂₅H₂₆FN₈O₂ (M + H)⁺: m/z = 489.2; found: 489.2. 38.3-(6-(1-(1,1- Dioxidotetrahydrothiophen- 3-y1)-1H-pyrazol-4-y1)-5-(((S)-tetrahydrofuran-3- yl)amino)pyrazolo[1,5-a]pyrimidin-3-y1)-4-fluoro- N,5-dimethylbenzamide

Calculated for C₂₆H₂₉FN₇O₄ (M + H)⁺: m/z = 554.2; found: 554.3. 39.(S)-3-(6-(1-(2- (Dimethylamino)-2- oxoethyl)-1H-pyrazol-4-y1)-5-((tetrahydrofuran-3- yl)amino)pyrazolo[1,5-a]pyrimidin-3-y1)-4-fluoro- N,5-dimethylbenzamide

Calculated for C₂₆H₃₀FN₈O₃ (M + H)⁺: m/z = 521.2; found: 521.3. 40.(S)-4-Fluoro-3-(6-(1-(2- hydroxy-2-methylpropy1)- 1H-pyrazol-4-y1)-5-((tetrahydrofuran-3- yl)amino)pyrazolo[1,5- a]pyrimidin-3-y1)-N,5-dimethylbenzamide

Calculated for C₂₆H₃₁FN₇O₃ (M + H)⁺: m/z = 508.2; found: 508.2. 41.4-Fluoro-N,3-dimethyl- 5-(6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-y1)-5-(((S)- tetrahydrofuran-3- yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

Calculated for C₂₆H₂₉FN₇O₃ (M + H)⁺: m/z = 506.2; found: 506.5. 42.(S)-4-Fluoro-N,3- dimethyl-5-(6-(2- methyloxazol-5-y1)-5-((tetrahydrofuran-3- yl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

Calculated for C₂₃H₂₄FN₆O₃ (M + H):⁺: m/z = 451.2; found: 451.1. 43.(S)-3-(6-(1-Ethy1-1H- pyrazol-3-y1)-5- ((tetrahydrofuran-3-yl)amino)pyrazolo[1,5- a]pyrimidin-3-y1)-4-fluoro- N,5-dimethylbenzamide

Calculated for C₂₄H₂₇FN₇O₂ (M + H)⁺: m/z = 464.2; found: 464.3. 44.(S)-4-Fluoro-N,3- dimethyl-5-(6-(pyridazin-4- yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

Calculated for C₂₃H₂₃FN₇O₂ (M + H)⁺: m/z = 448.2; found: 448.2.

Example 45.(S)-3-(5-(Ethylsulfonyl)-2,3-difluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-N-(tetrahydrofuran-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine

Step 1. (3-Bromo-4,5-difluorophenyl)(ethyl)sulfane

To a solution of 3-bromo-4,5-difluoroaniline (200 mg, 0.96 mmol) in MeCN(5 ml) was added 1,2-diethyldisulfane (142 μl, 1.15 mmol), followed bydropwise addition of tert-butyl nitrite (152 μl, 1.15 mmol), and thereaction mixture was stirred at 80° C. for 1 h. The reaction mixture wasconcentrated and the product was purified by flash chromatography (100%hexanes) to afford the title compound (131 mg, 54%). The product did notionize on LCMS. ¹H NMR (400 MHz, Chloroform-d) δ 7.28 (q, J=2.2 Hz, 1H),7.11 (ddd, J=9.6, 7.3, 2.2 Hz, 1H), 2.94 (q, J=7.3 Hz, 2H), 1.34 (t,J=7.3 Hz, 3H).

Step 2. 1-Bromo-5-(ethylsulfonyl)-2,3-difluorobenzene

To a solution of (3-bromo-4,5-difluorophenyl)(ethyl)sulfane (130 mg,0.51 mmol) in DCM (3 ml) was added m-CPBA (345 mg, 1.54 mmol), and thereaction mixture was stirred at room temperature for 2 h, at which pointTLC indicated complete consumption of starting material. The reactionmixture was diluted with DCM, treated with saturated Na₂S₂O₃ andsaturated NaHCO₃, and the biphasic mixture was vigorously stirred for 30min. The phases were separated and the organic phase was dried overMgSO₄, filtered, and concentrated. The product was purified by flashchromatography (0-100% EtOAc/hexanes). LMCS: No ionization.Characteristic peaks in ¹H NMR (400 MHz, Chloroform-d) δ 3.17 (q, J=7.5Hz, 2H), 1.34 (t, J=7.4 Hz, 3H).

Step 3.2-(5-(Ethylsulfonyl)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

1-Bromo-5-(ethylsulfonyl)-2,3-difluorobenzene (120 mg, 0.421 mmol) wascombined with bis(pinacolato)diboron (160 mg, 0.63 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (17 mg, 0.02 mmol) and potassium acetate (124 mg,1.26 mmol) in dioxane (4 ml) and the mixture was degassed under a streamof N₂. The reaction was heated to 100° C. overnight. The reactionmixture was diluted with EtOAc, filtered, and concentrated. The productwas purified by flash chromatography (0-100% EtOAc/hexanes). The productdid not ionize on LCMS, but disappearance of SM and appearance of asingle new peak indicated the reaction proceeded. The structure wasconfirmed by utilizing the product in the next step and successfullyobtaining the desired product.

Step 4.(S)-6-Chloro-3-(5-(ethylsulfonyl)-2,3-difluorophenyl)-N-(tetrahydrofuran-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine

A mixtureof(S)-3-bromo-6-chloro-N-(tetrahydrofuran-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(54 mg, 0.17 mmol, Example 34, Step 1),2-(5-(ethylsulfonyl)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(85 mg, 0.26 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (14 mg, 0.02 mmol), andsodium carbonate (54 mg, 0.51 mmol) in dioxane (2 ml) and water (0.5 ml)was thoroughly deoxygenated by three freeze-pump-thaw cycles, and heatedto 100° C. for 2 h. The reaction mixture was diluted with EtOAc andfiltered through a siliaprep thiol cartridge. The filtrate wasconcentrated and the product was purified by flash chromatography(0-100% EtOAc/hexanes followed by 0-10% MeOH/DCM). Approximately 50 mgof product was obtained, that contained about 30% of desired product andabout 70% of dehalogenated by-product. LCMS calculated forC₁₈H₁₈ClF₂N₄O₃S (M+H)⁺: m/z=443.1; found: 443.1.

Step 5.(S)-3-(5-(Ethylsulfonyl)-2,3-difluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-N-(tetrahydrofuran-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine

A mixture of(S)-6-chloro-3-(5-(ethylsulfonyl)-2,3-difluorophenyl)-N-(tetrahydrofuran-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(8 mg, 0.02 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11mg, 0.05 mmol), XPhos Pd G2 (0.7 mg, 0.9 μmol), and cesium carbonate (18mg, 0.05 mmol) in dioxane (1 ml) and water (0.5 ml) was sparged with N₂and heated to 100° C. for 2 h. The reaction was diluted with MeOH andfiltered through a thiol siliaprep cartridge. The product was purifiedby prep HPLC (pH 2). LCMS calculated for C₂₂H₂₃F₂N₆O₃S (M+H)⁺:m/z=489.1; found: 489.2.

Example 46.(S)-3-(5-(Ethylsulfonyl)-2,3-difluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine

This compound was synthesized by a procedure analogous to that describedfor Example 45, utilizing(S)-3-bromo-6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine(Example 11, Step 2) in Step 4. LCMS calculated for C₂₂H₂₂F₂N₅O₄S(M+H)⁺: m/z=490.1; found: 490.1.

Example 47.(S)-3-(Difluoromethyl)-4-fluoro-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

Step 1.(S)-3-(6-Chloro-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-5-(difluoromethyl)-4-fluoro-N-methylbenzamide

This compound was prepared by a procedure analogous to that described inExample 34, Step 2, utilizing3-(difluoromethyl)-4-fluoro-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate C). LCMS calculated for C₁₉H₁₈ClF₃N₅O₂(M+H)⁺: m/z=440.1;found: 440.1.

Step 2.(S)-3-(Difluoromethyl)-4-fluoro-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

This compound was prepared by a procedure analogous to that described inExample 34, Step 3, utilizing1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.LCMS calculated for C₂₃H₂₃F₃N₇O₂ (M+H)⁺: m/z=486.2; found: 486.2.

Examples 48-51

The compounds in the following table were prepared by a procedureanalogous to that described for Example 47, utilizing the appropriatecommercially available boronate or boronic acid in Step 2.

Example R LCMS 48. (S)-3-(Difluoromethyl)- 5-(6-(1-ethyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3- yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro- N-methylbenzamide

Calculated for C₂₄H₂₅F₃N₇O₂ (M + H)⁺: m/z = 500.2; found: 500.2. 49.3-(Difluoromethyl)-4- fluoro-N-methyl-5-(6-(1-(tetrahydrofuran-3-yl)-1H- pyrazol-4-yl)-5-(((S)- tetrahydrofuran-3-yl)amino)pyrazolo[1,5- a]pyrimidin-3-y1)benzamide

Calculated for C₂₆H₂₇F₃N₇O₃ (M + H)⁺: m/z = 542.2; found: 542.1. 50.(S)-3-(Difluoromethyl)- 4-fluoro-5-(6-(1-(2- methoxyethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3- yl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)-N-methylbenzamide

Calculated for C₂₅H₂₇F₃N₇O₃ (M + H)⁺: m/z = 530.2; found: 530.1.

Example 51.(S)-3-(3-(1H-Pyrazol-3-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine

Step 1.(S)-3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine

A mixture of3,5-dichloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine(86mg, 0.32 mmol, Example 1, Step 5), (S)-tetrahydrofuran-3-ol (130 μl,1.60 mmol), and cesium carbonate (157 mg, 0.48 mmol) in DMF (1.5 ml) washeated to 80° C. for 2 h. The reaction mixture was cooled to roomtemperature, diluted with DMF to a final concentration of 10 mg/mL, andfiltered. The solution of the product in DMF was used directly for thenext reactions. LCMS calculated for C₁₄H₁₅ClN₅O₂ (M+H)⁺: m/z=320.1;found: 320.0.

Step 2.(S)-3-(3-(1H-Pyrazol-3-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine

A mixture of(S)-3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine(10 mg, 0.031 mmol), (3-(1H-pyrazol-3-yl)phenyl)boronic acid (9 mg, 0.05mmol), XPhos Pd G2 (1.2 mg, 1.6 μmol), and cesium carbonate (30 mg, 0.09mmol) in dioxane (1 ml) and water (0.5 ml) was sparged with N₂ andheated to 100° C. for 2 h. The reaction was diluted with MeOH andfiltered through a thiol siliaprep cartridge. The product was purifiedby prep HPLC (pH 2). LCMS calculated for C₂₃H₂₂N₇O₂(M+H)⁺: m/z=428.2;found: 428.3.

Example 52.(S)-3,4-Difluoro-N-methyl-5-(6-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

Step 1.(S)-3-(6-Chloro-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4,5-difluoro-N-methylbenzamide

This compound was prepared by a procedure analogous to that describedfor Example 34, Step 2, utilizing Intermediate A instead of IntermediateB. LCMS calculated for C₁₈H₁₇ ClF₂N₅O₂(M+H)⁺: m/z=408.1; found: 408.2.

Step 2.(S)-3,4-Difluoro-N-methyl-5-(6-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

This compound was prepared by a procedure analogous to that describedfor Example 34, Step 3, utilizing3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridinefor the Suzuki coupling. LCMS calculated for C₂₇H₂₄F₂N₈O₂ (M+H)⁺:m/z=531.2; found: 531.2.

Examples 53-58

The compounds in the following table were prepared by a procedureanalogous to that described for Example 52, utilizing the appropriateboronate or boronic acid in Step 2.

Example R LCMS 53. (S)-3-(6-(1-Ethy1-1H- pyrazol-4-y1)-5-((tetrahydrofuran-3- yl)amino)pyrazolo[1,5- a]pyrimidin-3-y1)-4,5-difluoro-N- methylbenzamide

Calculated for C₂₃H₂₄F₂N₇O₂ (M + H)⁺: m/z = 468.2; found: 468.2. 54.(S)-3,4-Difluoro-N- methyl-5-(6-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H- pyrazol-4-y1)-5- ((tetrahydrofuran-3-yl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

Calculated for C₂₇H₃₀F₂N₇O₃ (M + H)⁺: m/z = 538.2; found: 538.2. 55.(S)-3,4-Difluoro-N- methy1-5-(6-(1-(2- morpholinoethyl)-1H-pyrazol-4-y1)-5- ((tetrahydrofuran-3- yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

Calculated for C₂₇H₃₁F₂N₈O₃ (M + H)⁺: m/z = 553.2; found: 553.2. 56.(S)-3,4-Difluoro-5-(6-(1- isopropyl-2-oxo-1,2- dihydropyridin-4-y1)-5-((tetrahydrofuran-3- yl)amino)pyrazolo[1,5- a]pyrimidin-3-y1)-N-methylbenzamide

Calculated for C₂₆H₂₇F₂N₆O₃ (M + H)⁺: m/z = 509.2; found: 509.1. 57.(S)-3,4-Difluoro-5-(6-(6- (2-hydroxypropan-2- yl)pyridin-3-y1)-5-((tetrahydrofuran-3- yl)amino)pyrazolo[1,5- a]pyrimidin-3-y1)-N-methylbenzamide

Calculated for C₂₆H₂₇F₂N₆O₃ (M + H)⁺: m/z = 509.2; found: 509.3. 58.(S)-3,4-Difluoro-N- methyl-5-(6-(2- methyloxazol-5-y1)-5-((tetrahydrofuran-3- yl)amino)pyrazolo[1,5- a]pyrimidin-3-yl)benzamide

Calculated for C₂₂H₂₁F₂N₆O₃ (M + H)⁺: m/z = 455.2; found: 455.2.

Example 59.(S)—N-Methyl-5-(6-(1-methyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide

Step 1.(S)-5-(6-Chloro-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide

A mixture of(S)-3-bromo-6-chloro-N-(tetrahydrofuran-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(60 mg, 0.19 mmol, Example 34, Step 1),N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (99mg, 0.38 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (15 mg, 0.02 mmol), and sodiumcarbonate (60 mg, 0.57 mmol) in dioxane (1.5 ml) and water (0.5 ml) wassparged with N₂ and heated to 100° C. for 2 h. The reaction mixture wasadsorbed onto silica gel directly. The product was purified by flashchromatography (0-100% EtOAc/hexanes followed by 0-20% MeOH/DCM) toafford the title compound (41 mg, 58%). LCMS calculated for C₁₇H₁₈ClN₆O₂(M+H)⁺: m/z=373.1; found: 373.1.

Step 2.(S)—N-Methyl-5-(6-(1-methyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide

A mixture of(S)-5-(6-chloro-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide(10 mg, 0.03 mmol),1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11mg, 0.05 mmol), XPhos Pd G2 (1.0 mg, 1.3 μmol), and cesium carbonate (26mg, 0.08 mmol) in dioxane (1 ml) and water (0.5 ml) was sparged with N₂and heated to 100° C. for 2 h. The reaction was diluted with MeOH andfiltered through a thiol siliaprep cartridge. The product was purifiedby prep HPLC (pH 2). LCMS calculated for C₂₁H₂₃N₈O₂ (M+H)⁺: m/z=419.2;found: 419.2.

Example 60.(S)—N-Methyl-5-(6-(2-methyl-2H-1,2,3-triazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide

This compound was prepared according to a procedure analogous to thatdescribed for Example 59, utilizing2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazolein Step 2. LCMS calculated for C₂₀H₂₂N₉O₂(M+H)⁺: m/z=420.2; found:420.2.

Example 61.(S)—N-Ethyl-5-(6-(1-methyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide

Step 1. 5-Bromo-N-ethylnicotinamide

To a suspension of 5-bromonicotinoyl chloride (200 mg, 0.91 mmol) in DCM(6 ml) was added DIPEA (190 μl, 1.09 mmol) and ethylamine (2M/THF, 544μl, 1.09 mmol) at 0° C., and the reaction mixture was allowed to warm toroom temperature. The reaction was quenched with saturated NaHCO₃ andextracted with DCM. The phases were separated and the organic phase waswashed with brine, dried over MgSO₄, filtered and concentrated. Theproduct was used without purification. LCMS calculated for C₈H₁₀BrN₂O(M+H)⁺: m/z=229.0; found: 229.0.

Step 2.N-Ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide

5-Bromo-N-ethylnicotinamide (50 mg, 0.22 mmol) was combined withbis(pinacolato)diboron (83 mg, 0.33 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (9 mg, 11 μmol) and potassium acetate (64 mg,0.66 mmol) in dioxane (3 ml) and the mixture was sparged with N₂ for 5min. The reaction was heated to 100° C. for 3 h. The reaction mixturewas diluted with EtOAc, filtered, and concentrated. The product was usedwithout purification. The following data is reported for thecorresponding boronic acid, which was the only observable species byLCMS. LCMS calculated for C₈H₁₂BN₂O₃ (M+H)⁺: m/z=195.1; found: 195.1.

Step 3.(S)—N-Ethyl-5-(6-(1-methyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide

This compound was prepared according to the procedure described forExample 59, utilizingN-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide.LCMS calculated for C₂₂H₂₅N₈O₂ (M+H)⁺: m/z=433.2; found: 433.2.

Example 62.(S)—N-Isopropyl-5-(6-(1-methyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide

This compound was prepared according the procedure described for Example61, utilizing isopropylamine instead of ethylamine in Step 1. LCMScalculated for C₂₃H₂₇NO₂ (M+H)⁺: m/z=447.2; found: 447.2.

Example 63.(S)-5-(6-(1-Isopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(methyl-d₃)nicotinamide

This compound was prepared by an identical procedure to that describedfor Example 9, utilizing Intermediate E in Step 3. LCMS calculated forC₂₃H₂₃D₃N₇O₃ (M+H)⁺: m/z=451.2; found: 451.2. ¹H NMR (600 MHz, DMSO-d₆)δ 9.40 (s, 2H), 8.99 (t, J=2.2 Hz, 1H), 8.84 (s, 1H), 8.75 (s, 1H), 8.68(s, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 5.80 (m, J=6.7, 4.4, 2.0 Hz, 1H),4.59 (hept, J=6.7 Hz, 1H), 4.18 (dd, J=10.7, 4.8 Hz, 1H), 4.08 (dd,J=10.7, 1.9 Hz, 1H), 3.96 (q, J=7.9 Hz, 1H), 3.88 (td, J=8.4, 4.7 Hz,1H), 2.50-2.42 (m, 1H), 2.32 (m, J=13.9, 6.9, 4.7, 1.9 Hz, 1H), 1.47 (d,J=6.7 Hz, 6H).

Example 64.4-Fluoro-3-(6-(1-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(((S)-tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-methyl-N-(methyl-d₃)benzamide

Step 1.tert-Butyl(3R,4S)-3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate

To a solution oftert-butyl(3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate(200 mg,0.91 mmol) in DCM (5 ml) at 0° C. was added DIPEA (239 μl, 1.37 mmol)and methanesulfonyl chloride (107 μl, 1.37 mmol), and the reactionmixture was allowed to warm to room temperature. After stirring for 30min, TLC indicated the reaction was complete. The reaction mixture wasquenched with saturated NaHCO₃ and extracted with DCM. The organic phasewas dried over MgSO₄, filtered and concentrated. The product waspurified by flash chromatography (0-50% EtOAc/hexanes) to afford thetitle compound (271 mg, quant.) as a white solid. LCMS calculated forC₇H₁₃FNO₅S (M-C₄H₇)⁺: m/z=242.0; found: 242.1.

Step 2. tert-Butyl(3R,4R)-3-fluoro-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a solution of tert-butyl(3R,4S)-3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (191mg, 0.64 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (125 mg,0.64 mmol) in acetonitrile (2 ml) was added cesium carbonate (419 mg,1.29 mmol) and the reaction mixture was stirred at 120° C. in themicrowave for 1 h. The reaction mixture was diluted with EtOAc,filtered, and concentrated. The residue was purified by flashchromatography (0-100% EtOAc/hexanes; slow gradient) to afford the titlecompound (62 mg, 24%). LCMS calculated for C₁₉H₃₂BFN₃O₄ (M+H)⁺:m/z=396.2; found: 396.3.

Step 3.(S)-3-(6-Chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-5-methyl-N-(methyl-d3)benzamide

A mixtureof(S)-3-bromo-6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine(56 mg, 0.176 mmol, Example 11, Step 2),4-fluoro-3-methyl-N-(methyl-d₃)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(63 mg, 0.21 mmol),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(12.5 mg, 0.018 mmol), and cesium fluoride (80 mg, 0.53 mmol) in n-BuOH(1.5 ml) and water (0.5 ml) was sparged with N₂ and heated to 65° C. for1 h. The reaction mixture was dry loaded onto silica gel and the productwas purified by flash chromatography (0-100% EtOAc/hexanes followed by0-20% MeOH/DCM) to afford the title compound (45 mg, 63%). LCMScalculated for C₁₉H₁₆D₃ClFN₄O₃ (M+H)⁺: m/z=408.1; found: 408.4.

Step 4. tert-Butyl(3R,4R)-3-fluoro-4-(4-(3-(2-fluoro-3-methyl-5-((methyl-d3)carbamoyl)phenyl)-5-(((S)-tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

A mixture of(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-5-methyl-N-(methyl-d₃)benzamide(15 mg, 0.04 mmol), tert-butyl(3R,4R)-3-fluoro-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(16 mg, 0.04 mmol), XPhos Pd G2 (1.4 mg, 1.8 μmol), and cesium carbonate(36 mg, 0.11 mmol) in dioxane (2 ml) and water (0.5 ml) was sparged withN₂ and heated to 100° C. for 1 h. The reaction mixture was filteredthrough a thiol siliaprep cartridge, concentrated, and the product wasused without purification. LCMS calculated for C₃₂H₃₅D₃F₂N₇O₅ (M+H)⁺:m/z=641.3; found: 641.3.

Step 5.4-Fluoro-3-(6-(1-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(((S)-tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-methyl-N-(methyl-d₃)benzamide

A solution of tert-butyl(3R,4R)-3-fluoro-4-(4-(3-(2-fluoro-3-methyl-5-((methyl-d₃)carbamoyl)phenyl)-5-(((S)-tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(24 mg, 0.04 mmol) in MeOH (2 ml) was treated with HCl (4M/dioxane, 3ml) and stirred at room temperature for 30 min. The reaction mixture wasconcentrated and the product was used without purification.

The amine obtained above was dissolved in MeOH (2 ml) and formaldehyde(37 wt % in water, 28 μl, 0.38 mmol) was added, followed by sodiumcyanoborohydride (24 mg, 0.38 mmol). The reaction mixture was stirred atroom temperature for 1 h, then filtered and purified by prep HPLC (pH 2)to afford the title compound (7.1 mg, 34%). LCMS calculated forC₂₈H₂₉D₃F₂N₇O₃ (M+H)⁺: m/z=555.3; found: 555.1.

Example 65.4-Fluoro-3-(6-(1-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(((S)-tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,5-dimethylbenzamide

This compound was prepared by an identical procedure to that describedfor Example 64, utilizing(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-N,5-dimethylbenzamide(Example 34, Step 2) in Step 4. LCMS calculated for C₂₈H₃₃F₂N₈O₂ (M+H)⁺:m/z=551.3; found: 551.3.

Example 66.3-(6-(6-(((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)pyridin-3-yl)-5-(((S)-tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-(difluoromethyl)-4-fluoro-N-(methyl-d₃)benzamide

Step 1.(1R,4R)-5-((5-Bromopyridin-2-yl)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane

To a solution of 5-bromopicolinaldehyde (50 mg, 0.27 mmol) in DCE (1 ml)was added (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (36 mg,0.27 mmol), sodium triacetoxyborohydride (85 mg, 0.40 mmol), andtriethylamine (37 μl, 0.27 mmol), and the reaction mixture was stirredat room temp for 3 h. The reaction was quenched with saturated NaHCO₃and extracted with DCM. The organic phase was dried over MgSO₄,filtered, and concentrated. The product was used without purification.LCMS calculated for C₁₁H₁₄BrN₂O (M+H)⁺: m/z=269.1; found: 269.0.

Step 2.(1R,4R)-5-((5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane

(1R,4R)-5-((5-Bromopyridin-2-yl)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane(72 mg, 0.29 mmol) was combined with bis(pinacolato)diboron (102 mg,0.40 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (11 mg, 0.01 mmol) and potassium acetate (79 mg,0.80 mmol) in dioxane (3 ml) and the mixture was sparged with N₂. Thereaction was heated to 100° C. for 3 h. The reaction mixture was dilutedwith EtOAc, filtered, concentrated. The product was used withoutpurification. The following data is reported for the correspondingboronic acid, which was the only observable species by LCMS. LCMScalculated for C₁₁H₁₆BN₂O₃ (M+H)⁺: m/z=235.1; found: 235.2.

Step 3.(S)-3-(6-Chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-(difluoromethyl)-4-fluoro-N-(methyl-d₃)benzamide

This compound was prepared by an identical procedure to that describedfor Example 23, Step 1, utilizing Intermediate G instead of IntermediateC. LCMS calculated for C₁₉H₁₄D₃ClF₃N₄O₃ (M+H)⁺: m/z=444.1; found: 444.1.

Step 4.3-(6-(6-(((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)pyridin-3-yl)-5-(((S)-tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-(difluoromethyl)-4-fluoro-N-(methyl-d₃)benzamide

A mixture of(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-(difluoromethyl)-4-fluoro-N-(methyl-d₃)benzamide(45 mg, 0.10 mmol),(1R,4R)-5-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane(48 mg, 0.15 mmol), XPhos Pd G2 (4 mg, 5.0 μmol), and cesium carbonate(99 mg, 0.30 mmol) in dioxane (1.5 ml) and water (0.5 ml) was spargedwith N₂ and heated to 100° C. for 1 h. The reaction mixture was dilutedwith MeOH, filtered through a thiol siliaprep cartridge, and the productwas purified by prep HPLC. LCMS calculated for C₃₀H₂₇D₃F₃N₆O₄ (M+H)⁺:m/z=598.2; found: 598.3. ¹H NMR (500 MHz, DMSO-d₆) δ 9.31 (s, 1H), 9.18(dd, J=7.1, 2.2 Hz, 1H), 8.98 (d, J=2.3 Hz, 1H), 8.56 (d, J=3.2 Hz, 1H),8.48 (s, 1H), 8.25 (dd, J=8.1, 2.3 Hz, 1H), 8.02-7.97 (m, 1H), 7.68 (d,J=8.1 Hz, 1H), 7.32 (t, J=54.3 Hz, 1H), 5.80 (td, J=5.0, 2.5 Hz, 1H),4.78 (d, J=14.7 Hz, 1H), 4.71 (d, J=2.5 Hz, 1H), 4.66 (d, J=14.6 Hz,1H), 4.53 (s, 1H), 4.26 (d, J=9.9 Hz, 1H), 4.14 (dd, J=10.7, 4.9 Hz,1H), 3.97 (dd, J=10.7, 1.9 Hz, 1H), 3.89-3.78 (m, 3H), 3.52-3.39 (m,2H), 2.50-2.43 (m, 1H), 2.39 (d, J=11.8 Hz, 1H), 2.19-2.09 (m, 2H).

Example 67.(S)-4-Fluoro-3-(6-(2-(1-isopropylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-5-methyl-N-(methyl-d₃)benzamide

Step 1. tert-Butyl4-(4,5-dibromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate

A mixture of 4,5-dibromo-2H-1,2,3-triazole (100 mg, 0.44 mmol),tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (148 mg, 0.53mmol), and cesium carbonate (172 mg, 0.53 mmol) in DMF (4 ml) was heatedto 100° C. for 3 h. The reaction mixture was filtered and concentratedto dryness. The residue was purified by flash chromatography (0-100%EtOAc/hexanes) to afford the title compound (140 mg, 77%). LCMScalculated for C₈H₁₁Br₂N₄O₂(M-C₄H₇)⁺: m/z=352.9; found: 352.9.

Step 2. tert-Butyl4-(4-bromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-(4,5-dibromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (140 mg,0.34 mmol) in THF (3 ml) at −78° C. was added n-butyllithium (143 μl,0.36 mmol) and the reaction mixture was stirred at −78° C. for 20 min.LCMS indicated about equal ratios of starting material, desired product,and an unknown by-product. Additional n-butyllithium (143 μl, 0.36 mmol)was added and stirring was continued at −78° C. for another 20 min. Thereaction mixture was quenched with saturated NH₄Cl, warmed to roomtemperature, and extracted with EtOAc. The layers were separated and theorganic phase was washed with brine, dried over MgSO₄, filtered andconcentrated. The product was purified by flash chromatography (0-50%EtOAc/hexanes) to afford the title compound (37 mg, 32%). LCMScalculated for C₈H₁₂BrN₄O₂ (M-C₄H₇)⁺: m/z=275.0; found: 275.1.

Step 3. tert-Butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-(4-bromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (36 mg, 0.11mmol) in THE (3 ml) at −78° C. was added n-butyllithium (65 μl, 0.16mmol) and the reaction mixture was stirred at −78° C. for 15 min.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (44 μl, 0.22 mmol)was added and the reaction mixture was stirred while the temperaturegradually warmed to room temperature over 2 h. The reaction was quenchedwith saturated NH₄Cl. EtOAc was added and layers were separated. Theorganic phase was washed with brine, dried over MgSO₄, filtered andconcentrated. The product was used without purification. The followingdata is reported for the corresponding boronic acid, which was the onlyobservable species by LCMS. LCMS calculated for C₁₂H₂₂BN₄O₄ (M-C₄H₇)⁺:m/z=297.2; found: 297.2.

Step 4.(S)-3-(6-Chloro-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-5-methyl-N-(methyl-d₃)benzamide

A mixture of(S)-3-bromo-6-chloro-N-(tetrahydrofuran-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine(85 mg, 0.27 mmol, Example 34, Step 1),4-fluoro-3-methyl-N-(methyl-d₃)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(95 mg, 0.32 mmol),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(19 mg, 2.7 μmol), and cesium fluoride (122 mg, 0.80 mmol) in BuOH (3.5ml) and water (0.5 ml) was sparged with N₂ and heated to 70° C. for 1 h.The reaction mixture was directly dry loaded onto silica gel andpurified by flash chromatography (0-100% EtOAc/hexanes followed by 0-20%MeOH/DCM) to afford the title compound (63 mg, 58%). LCMS calculated forC₁₉H₁₇D₃ClFN₅O₂ (M+H)⁺: m/z=407.1; found: 407.2.

Step 5.tert-Butyl(S)-4-(4-(3-(2-fluoro-3-methyl-5-((methyl-d₃)carbamoyl)phenyl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate

A mixture of(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-5-methyl-N-(methyl-d₃)benzamide(20 mg, 0.05 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate(28 mg, 0.07 mmol), XPhos Pd G2 (1.9 mg, 2.5 μmol), and cesium carbonate(48 mg, 0.15 mmol) in dioxane (2.5 ml) and water (0.5 ml) was spargedwith N₂ and heated to 100° C. for 1 h. The reaction mixture was dilutedwith MeOH, filtered through a thiol siliaprep cartridge, andconcentrated. The product was used without purification. LCMS calculatedfor C₃₁H₃₆D₃FN₉O₄ (M+H)⁺: m/z=623.3; found: 623.4.

Step 6.(S)-4-Fluoro-3-(6-(2-(1-isopropylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-5-methyl-N-(methyl-d₃)benzamide

A solution of tert-butyl(S)-4-(4-(3-(2-fluoro-3-methyl-5-((methyl-d₃)carbamoyl)phenyl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate(22 mg, 0.04 mmol) in MeOH (2 ml) was treated with HCl (4M/dioxane, 2ml) and stirred at room temperature for 30 min. The reaction mixture wasconcentrated and the product was used without purification.

The amine obtained above was dissolved in MeOH (2 ml). Acetone (52 μL,0.71 mmol) was added, followed by sodium cyanoborohydride (22 mg, 35μmol). The reaction mixture was stirred at room temperature for 4 h,then filtered and purified by prep HPLC. LCMS calculated forC₂₉H₃₄D₃FN₉O₂ (M+H)⁺: m/z=565.3; found: 565.4.

Example 68.(S)-4-Fluoro-3-(6-(2-(1-isopropylpiperidin-4-yl)oxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-5-methyl-N-(methyl-d₃)benzamide

Step 1. Benzyl 4-((2,2-dimethoxyethyl)carbamoyl)piperidine-1-carboxylate

To a solution of 1-((benzyloxy)carbonyl)piperidine-4-carboxylic acid(200 mg, 0.76 mmol) and HATU (318 mg, 0.84 mmol) in DMF (5 ml) was addedDIPEA (265 μl, 1.52 mmol), followed by 2,2-dimethoxyethan-1-amine (103μl, 0.84 mmol), and the reaction mixture was stirred at room temperaturefor 30 min. The reaction was quenched with water and extracted withEtOAc. The layers were separated and the organic phase was washed withbrine, dried over MgSO₄, filtered and concentrated. The residue waspurified by flash chromatography (0-100% EtOAc/hexanes) to afford thetitle compound (220 mg, 83%) as a colorless oil. LCMS calculated forC₁₈H₂₆N₂O₅Na (M+Na)⁺: m/z=373.2; found: 373.3.

Step 2. 2-(Piperidin-4-yl)oxazole

Benzyl 4-((2,2-dimethoxyethyl)carbamoyl)piperidine-1-carboxylate (200mg, 0.57 mmol) was dissolved in Eaton's reagent (3 mL, 18.9 mmol) andheated to 130° C. for 6 h. The reaction mixture was cooled to 0° C. andquenched with 1M NaOH. The aqueous phase was washed with EtOAc andconcentrated. The product was used without purification. LCMS calculatedfor C₈H₁₃N₂O (M+H)⁺: m/z=153.1; found: 153.0.

Step 3. tert-Butyl 4-(oxazol-2-yl)piperidine-1-carboxylate

To a solution of 2-(piperidin-4-yl)oxazole (90 mg, 0.59 mmol) in THF (3ml)/water (3 ml) was added sodium carbonate (75 mg, 0.71 mmol) anddi-tert-butyl dicarbonate (165 μl, 0.71 mmol). The reaction mixture wasstirred for 30 min at room temperature. The reaction mixture waspartitioned between water and EtOAc, and the layers were separated. Theaqueous phase was extracted with EtOAc and the combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentrated.The residue was purified by flash chromatography (0-50% EtOAc/hexanes)to afford the title compound (71 mg, 48% over 2 steps). LCMS calculatedfor C₉H₁₂N₂O₃ (M-C₄H₇)⁺: m/z=197.1; found: 197.2.

Step 3. tert-Butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazol-2-yl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(oxazol-2-yl)piperidine-1-carboxylate (20mg, 0.08 mmol) in THE (3 ml) at −78° C. was added n-butyllithium (48 μl,0.12 mmol), and the reaction mixture was stirred at −78° C. for 20 min.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (32 μl, 0.16 mmol)was added and the reaction mixture was allowed to warm to roomtemperature. The reaction was quenched with saturated NH₄Cl andextracted with EtOAc. The layers were separated and the organic phasewas washed with brine, dried over MgSO₄, filtered and concentrated. Theproduct was used without purification. The following data is reportedfor the corresponding boronic acid, which was the only observablespecies by LCMS. LCMS calculated for C₉H₁₄BN₂O₅ (M-C₄H₇)⁺: m/z=241.1;found: 241.1.

Step 4. tert-Butyl(S)-4-(5-(3-(2-fluoro-3-methyl-5-((methyl-d₃)carbamoyl)phenyl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)oxazol-2-yl)piperidine-1-carboxylate

A mixture of(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-5-methyl-N-(methyl-d₃)benzamide(15 mg, 0.04 mmol), tert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazol-2-yl)piperidine-1-carboxylate(21 mg, 0.06 mmol), XPhos Pd G2 (2.9 mg, 3.7 μmol), and cesium carbonate(36 mg, 0.11 mmol) in dioxane (2.5 ml) and water (0.5 ml) was spargedwith N₂ and heated to 100° C. for 1 h. The reaction mixture waspartitioned between water and EtOAc, and the layers were separated. Theaqueous phase was extracted with EtOAc and the combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentrated.The product used without purification. LCMS calculated for C₃₂H₃₆D₃FN₇O₅(M+H)⁺: m/z=623.3; found: 623.4.

Step 5.(S)-4-Fluoro-3-(6-(2-(1-isopropylpiperidin-4-yl)oxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-5-methyl-N-(methyl-d₃)benzamide

A solution of tert-butyl(S)-4-(5-(3-(2-fluoro-3-methyl-5-((methyl-d₃)carbamoyl)phenyl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)oxazol-2-yl)piperidine-1-carboxylate(22 mg, 0.04 mmol) in MeOH (2 ml) was treated with HCl (4M/dioxane, 2ml) and stirred at room temperature for 30 min. The reaction mixture wasconcentrated and the product was used without purification.

The amine obtained above was dissolved in MeOH (2 ml). Acetone (52 μl,0.7 mmol) was added, followed by sodium cyanoborohydride (22 mg, 0.4mmol). The reaction mixture was stirred at room temperature overnight,then filtered and purified by prep HPLC. LCMS calculated forC₃₀H₃₄D₃FN₇O₃ (M+H)⁺: m/z=565.3; found: 565.4.

Example 69.(S)-4-Fluoro-3-(6-(2-(4-fluoro-1-methylpiperidin-4-yl)oxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,5-dimethylbenzamide

Step 1. tert-Butyl 4-hydroxy-4-(oxazol-2-yl)piperidine-1-carboxylate

To a solution of oxazole (100 mg, 1.45 mmol) in THE (6 ml) at roomtemperature was added borane tetrahydrofuran complex (1.45 ml, 1.45mmol) dropwise. The reaction mixture was stirred at room temperature for30 min and cooled to −78° C. Next, n-butyllithium (2.5M/hexanes, 0.58ml, 1.45 mmol) was added dropwise, and the reaction was stirred at thistemperature for 30 min. A solution of tert-butyl4-oxopiperidine-1-carboxylate (289 mg, 1.45 mmol) in THF (3 mL) was thenslowly added, and the reaction mixture was stirred for an additional 30min at −78° C. The reaction was quenched with 5% AcOH/EtOH (2 mL total)and allowed to warm to room temperature. The reaction mixture waspartitioned between water and EtOAc, and the layers were separated. Theaqueous phase was extracted with EtOAc and the combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentrated.The residue was purified by flash chromatography (0-100% EtOAc/hexanes)to afford the title compound (330 mg, 85%). LCMS calculated forC₉H₁₃N₂O₄ (M-C₄H₇)⁺: m/z=213.1; found: 213.2.

Step 2. tert-Butyl 4-fluoro-4-(oxazol-2-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-hydroxy-4-(oxazol-2-yl)piperidine-1-carboxylate (110 mg, 0.41 mmol) inDCM (3 ml) at 0° C. was added DAST (108 μl, 0.82 mmol) and the reactionmixture was stirred at 0° C. for 15 min before being warmed to roomtemperature. After 1 h, the solution was cooled back to 0° C., quenchedwith saturated NaHCO₃, and extracted with DCM. The organic phase wasdried over MgSO₄, filtered, and concentrated. The product was purifiedby flash chromatography (0-100% EtOAc/hexanes) to afford the titlecompound (76 mg, 69%). LCMS calculated for C₉H₁₂FN₂O₃ (M-C₄H₇)⁺:m/z=215.1; found: 215.1.

Step 3. tert-Butyl4-fluoro-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazol-2-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-fluoro-4-(oxazol-2-yl)piperidine-1-carboxylate (76 mg, 0.28 mmol) inTHE (3 ml) at −78° C. was added n-butyllithium (225 μl, 0.56 mmol)(color change observed) and the reaction mixture was stirred at thistemperature for 20 min.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (143 μl, 0.70 mmol)was added and stirred while the reaction mixture gradually warmed toroom temperature over 2 h. The reaction was quenched with saturatedNH₄Cl. EtOAc was added and the layers were separated. The organic phasewas washed with brine, dried over MgSO₄, filtered and concentrated. Theproduct was used without purification. The following data is reportedfor the corresponding boronic acid, which was the only observablespecies by LCMS. LCMS calculated for C₉H₁₃BFN₂O₅ (M-C₄H₇)⁺: m/z=259.1;found: 259.1.

Step 4. tert-Butyl(S)-4-fluoro-4-(5-(3-(2-fluoro-3-methyl-5-(methylcarbamoyl)phenyl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)oxazol-2-yl)piperidine-1-carboxylate

This compound was prepared according to the procedure described inExample 68, Step 4, utilizing tert-butyl4-fluoro-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazol-2-yl)piperidine-1-carboxylate,(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-5-methyl-N-(methyl)benzamide,XPhos Pd G2, and cesium carbonate in dioxane and water. LCMS calculatedfor C₃₂H₃₈F₂N₇O₅ (M+H)⁺: m/z=638.3; found: 638.4.

Step 5.(S)-4-Fluoro-3-(6-(2-(4-fluoro-1-methylpiperidin-4-yl)oxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,5-dimethylbenzamide

This compound was prepared according to the procedure described inExample 68, Step 5, utilizing formaldehyde instead of acetone for thereductive amination. LCMS calculated for C₂₈H₃₂F₂N₇O₃ (M+H)⁺: m/z=552.3;found: 552.4.

Example 70.(S)-4-Fluoro-N,3-dimethyl-5-(6-(2-(4-methylpiperazin-1-yl)oxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

Step 1. tert-Butyl 4-(oxazol-2-yl)piperazine-1-carboxylate

A mixture of 2-chlorooxazole hydrochloride (100 mg, 0.72 mmol),tert-butyl piperazine-1-carboxylate (200 mg, 1.07 mmol), RuPhos Pd G4(30 mg, 0.04 mmol), and cesium carbonate (698 mg, 2.14 mmol) in dioxane(3 ml) was heated to 100° C. for 1 h. The reaction mixture was dilutedwith EtOAc, filtered and concentrated. The product was purified by flashchromatography (0-100% EtOAc/hexanes) to afford the title compound (72mg, 40%). LCMS calculated for C₁₂H₂₀N₃O₃ (M+H)⁺: m/z=254.1; found:254.2.

Step 2. tert-Butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazol-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl 4-(oxazol-2-yl)piperazine-1-carboxylate (7′mg, 0.28 mmol) in THF (3 ml) at −78° C. was added n-butyllithium (221μl, 0.55 mmol), and the reaction mixture was stirred at −78° C. for 20min. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (141 μl, 0.69mmol) was added and the reaction mixture was allowed to warm to roomtemperature. The reaction was quenched with saturated NH₄Cl andextracted with EtOAc. The layers were separated and the organic phasewas washed with brine, dried over MgSO₄, filtered and concentrated. Theproduct was used without purification. The following data is reportedfor the corresponding boronic acid, which was the only observablespecies by LCMS. LCMS calculated for C₁₂H₂₁BN₃O₅ (M+H)⁺: m/z=298.2;found: 298.1.

Step 3. tert-Butyl(S)-4-(5-(3-(2-fluoro-3-methyl-5-(methylcarbamoyl)phenyl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)oxazol-2-yl)piperazine-1-carboxylate

This compound was prepared according to the procedure described inExample 68, Step 4, utilizing tert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazol-2-yl)piperazine-1-carboxylate,(S)-3-(6-chloro-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-5-methyl-N-(methyl)benzamide,XPhos Pd G2, and cesium carbonate in dioxane and water. LCMS calculatedfor C₃₁H₃₈FN₈O₅ (M+H)⁺: m/z=621.3; found: 621.4.

Step 4.(S)-4-Fluoro-N,3-dimethyl-5-(6-(2-(4-methylpiperazin-1-yl)oxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide

This compound was prepared according to the procedure described inExample 68, Step 5, utilizing formaldehyde instead of acetone for thereductive amination. LCMS calculated for C₂₇H₃₂FN₈O₃ (M+H)⁺: m/z=535.3;found: 535.4.

Example A: FGFR Enzymatic Assay

The inhibitor potency of the exemplified compounds was determined in anenzyme discontinuous assay that measures peptide phosphorylation usingFRET measurements to detect product formation. Inhibitors were seriallydiluted in DMSO and a volume of 0.2 μL was transferred to the wells of a384-well plate. A 5 μL/well volume of enzyme isoforms of FGFR (-1, -2,-3 wild-type and mutant isoforms, -4) including phosphorylated andun-phosphorylated proteins diluted in assay buffer (50 mM HEPES, 10 mMMgCl₂, 1 mM EGTA, 0.01% Tween-20, 5 mM DTT, pH 7.5) was added to theplate and pre-incubated with inhibitor for 5 to 15 minutes at ambienttemperature. Appropriate controls (enzyme blank and enzyme with noinhibitor) were included on the plate. The reaction was initiated by theaddition of a 5 μL/well volume containing both biotinylatedEQEDEPEGDYFEWLE peptide substrate (SEQ ID NO: 1) and ATP in assaybuffer. The 10 μL/well reaction concentration of the peptide substratewas 500 nM whereas the ATP concentration was maintained near or belowthe ATP Km. The ATP Km values were pre-determined in a separate seriesof experiments. The reaction plate was incubated at 25° C. for 1 hr andthe reactions were ended with the addition of 5 μL/well of quenchsolution (50 mM Tris, 150 mM NaCl, 0.5 mg/mL BSA, pH 7.8; 45 mM EDTA,600 nM staurosporin, with Perkin Elmer Lance Reagents at 3.75 nMEu-antibody PY20 and 180 nM APC-Streptavidin). The plate was allowed toequilibrate for ˜10 minutes at ambient temperature before scanning on aPheraStar plate reader (BMG Labtech) instrument.

Either GraphPad prism or XLfit was used to analyze the data. The IC₅₀values were derived by fitting the data to a four parameter logisticequation producing a sigmoidal dose-response curve with a variable Hillcoefficient. Prism equation: Y=Bottom+(Top−Bottom)/(1+10{circumflex over( )}((Log IC₅₀−X)*Hill slope)); XLfit equation:Y=(A+((B−A)/(1+((X/C){circumflex over ( )}D)))) where X is the logarithmof inhibitor concentration and Y is the response. Compounds having anIC₅₀ of 1 μM or less are considered active.

Table 1 provides IC₅₀ data for compounds of the invention assayed in theFGFR Enzymatic Assay after dilution in assay buffer, added to the plateand pre-incubated for 4 hours.

The symbol: “+” indicates an IC₅₀ less than 10 nM; “++” indicates anIC₅₀ greater than or equal to 10 nM but less than 30 nM; “+++” indicatesan IC₅₀ greater than or equal to 30 nM but less than 200 nM; and “++++”indicates an IC₅₀ greater than or equal to 200 nM.

The FGFR3 data in Table 1 was measured in wild-type un-phosphorylatedFGFR3 protein.

TABLE 1 Example FGFR3 IC₅₀ FGFR1 IC₅₀ FGFR2 IC₅₀ FGFR4 IC₅₀ No. (nM)(nM) (nM) (nM) 1 + +++ + 2 + +++ + 3 + +++ + ++++ 4 + +++ + +++ 5 + + +6 + ++ + 7 + +++ 8 + +++ 9 + ++ + 10 + +++ 11 + + + 12 + + + 13 + ++ +14 + + + 15 + +++ + 16 + +++ + 17 + + + 18 + +++ + 19 + +++ + 20 + +++ +21 + +++ + 22 + ++ + 23 + +++ + 24 ++ ++++ ++ 25 + +++ + 26 + + + 27 ++++++ ++ 28 + ++++ ++ 29 +++ ++++ +++ 30 + +++ ++ 31 + ++ + 32 ++++ +++++++ 33 + ++ + +++ 34 + ++ + +++ 35 + ++ + ++++ 36 + +++ + 37 + ++ + 38 ++++ + 39 + ++ + 40 + ++ + +++ 41 + +++ + +++ 42 + ++ + +++ 43 + ++ + +++44 ++ ++++ ++ 45 + ++ + ++++ 46 ++ ++ + ++++ 47 + ++ + 48 + ++ + 49 +++ + 50 + ++ + 51 + ++ + ++++ 52 + + + 53 + ++ + ++++ 54 + + + 55 + + ++++ 56 + ++ + 57 + +++ + 58 + + + +++ 59 + + + ++ 60 + +++ + ++++ 61 ++++ + +++ 62 ++ +++ ++ ++++ 63 + ++ + +++ 64 + + + ++ 65 + ++ + +++ 66 ++++ + +++ 67 + + + 68 + +++ + 69 + +++ + 70 + +++ +

Example B: Luminescent Viability Assay

RT112 cells are purchased from ATCC (Manassas, Va.) and maintained inRPMI, 10% FBS (Gibco/Life Technologies). To measure the effect of testcompounds on the viability of cells, the cells are plated with RPMI 10%FBS (5×10³ cells/well/in 50 μL) into black 96-well Greiner polystyrenein the presence or absence of 50 ul of a concentration range of testcompounds. After 3 days, 100 ul of CellTiter-Glo Reagent (Promega) isadded. Luminescence is read with a TopCount (PerkinElmer). IC₅₀determination is performed by fitting the curve of percent inhibitionversus the log of the inhibitor concentration using the GraphPad Prism5.0 software.

Example C: pFGFR2 and pFGFR1,3 Functional Cell HTRF Assay

To measure phosphorylated Fibroblast Growth Factor Receptor 2 (FGFR2),KATOIII cells (Human Gastric Carcinoma) are purchased from ATCC andmaintained in Iscove's with 20% FBS (Gibco/Life Technologies). For thepFGFR2 assay, KATOIII cells are plated overnight in 5% FBS and Iscove'smedium at 5×10⁴ cells/well into Corning 96-well flat-bottom tissueculture treated plates. The next morning, 50 μl of fresh media with 0.5%FBS is incubated in the presence or absence of a concentration range oftest compounds also at 50 ul, for 1 hour at 37° C., 5% CO2. Cell arewashed with PBS, lysed with Cell Signaling Lysis Buffer with standardProtease inhibitors for 45 min at room temperature. 4 μl total of CisBio Anti Phospho-YAP d2 and Cis Bio Anti Phospho-YAP Cryptate togetherare added to the lysate and mixed well (following directions of thekit). 16 μl is then transferred to 384 well Greiner white plates andstored at 4° C. overnight in the dark. Plates are read on the Pherastarplate reader at 665 nm and 620 nm wavelengths. IC₅₀ determination isperformed by fitting the curve of inhibitor percent inhibition versusthe log of the inhibitor concentration using the GraphPad Prism 5.0software.

To measure phosphorylated Fibroblast Growth Factor Receptor 3 (FGFR3),in house stable cell lines BAF3-TEL-FGFR1 or BAF3-TEL-FGFR3 aremaintained in RPMI with 10% FBS and 1 ug/ml puromycin (Gibco/LifeTechnologies). For the assay, 12 nl of BAF3-TEL-FGFR1 or BAF3-TEL-FGFR3cells in serum free and puromycin free RPMI media at 1×10⁶ cell/ml areadded to 384 Greiner white plate already containing 20 nl dots ofcompounds at a concentration range. The plates are gently shaken (100rpm) for 2 minutes at room temperature to mix well and incubate for 2hours in a single layer at 37° C., 5% CO2. 4 μl/well of 1/25 dilution oflysis buffer #3 (Cis Bio) is added with standard Protease inhibitors andshaken at 200 rpm at room temperature for 20 minutes. 4 μl total of theCis Bio Tb-pFGFR Ab (Ong) and d2-FGFR3 (ing) together are added to thelysate and mixed well. The plates are sealed and incubated at roomtemperature overnight in the dark. The plates are read on the Pherastarplate reader at 665 nm and 620 nm wavelengths. IC₅₀ determination isperformed by fitting the curve of inhibitor percent inhibition versusthe log of the inhibitor concentration using the GraphPad Prism 5.0software.

Example D: pFGFR3 Functional Whole Blood HTRF Assay

To measure phosphorylated Fibroblast Growth Factor Receptor 3 (FGFR3) ina whole blood assay, in house stable cell lines BAF3-TEL-FGFR3 aremaintained in RPMI with 10% FBS and 1 μg/ml puromycin (Gibco/LifeTechnologies). For the assay, 100 ul BAF3-TEL-FGFR3 cells in 10% FBS andpuromycin free RPMI media at 5×10⁴ cell/well are added to fibronectincoated 96 well tissue culture plate (5 ug/ml) overnight at 37° C., 5%CO2. The next day, serum is separated from the top of the blood by a lowspeed spin, 1200, RPM, and heat inactivated by incubating at 56° C. for15 minutes. 30 μl of the cooled serum is added to a 96 well plate predotted with 70 nM dots of compounds at a concentration range. Cellplates are washed gently with media, all the blood/compound mixture isadded to the plates, and the plates are incubated for 2 hours at 37° C.,5% CO2. Blood from the plate is gently washed twice by adding media tothe side of the wells and then dumping media from the plate, andallowing the plate to briefly sit on a paper towel to drain. 70 μl/wellof 1× of lysis buffer #1 (Cis Bio) are added with standard Proteaseinhibitors, and are shaken at 400 rpm at room temperature for 30minutes. Following lysis, the plate is spun down for 5 minutes and 16 uLof lysate is transferred into a 384-well small volume plate. 4 μl totalof the Cis Bio Tb-pFGFR Ab (Ong) and d2-FGFR3 (Ing) together are addedto the lysate and mixed well. The plates are sealed and incubated atroom temperature overnight in the dark. Plates are read on the Pherastarplate reader at 665 nm and 620 nm wavelengths. IC₅₀ determination isperformed by fitting the curve of inhibitor percent inhibition versusthe log of the inhibitor concentration using the GraphPad Prism 5.0software.

Example E: KATOIII Whole Blood pFGFR2α ELISA Assay

To measure tyrosine-phosphorylated Fibroblast Growth Factor Receptor 2alpha (FGFR2α) in KATO III spiked whole blood assay, KATO III cells arepurchased from ATCC and maintained in Iscove's medium with 20% FBS(Gibco/Life Technologies). To measure the inhibition of FGFR2α activityof test compounds, the cells are resuspended with Iscove's, 0.2% FBS at5×10⁶ cells/ml. 50 μL of the cells are then spiked into a 96-deep well 2ml polypropylene assay block (Costar,) in the presence or absence of aconcentration range of test compounds and 300 ul human heparinized wholeblood (Biological Specialty Corp, Colmar Pa.). After 4 hours incubationin 37° C., the red cells are lysed using Qiagen EL buffer and the celllysates are resuspended in lysis buffer (Cell Signaling) containingstandard protease inhibitor cocktail (Calbiochem/EMD,) and PMSF (Sigma)for 30 minutes ice. The lysates are transferred to a standard V bottompropylene tissue culture plate and frozen overnight at −80° C. Samplesare tested an in an R & D Systems DuoSet IC Human Phospho-FGF R2α ELISAand the plate is measured using a SpectraMax M5 microplate set to 450 nmwith a wavelength correction of 540. IC₅₀ determination is performed byfitting the curve of inhibitor percent inhibition versus the log of theinhibitor concentration using the GraphPad Prism 5.0 software.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Cy¹ is selectedfrom C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 5-10 memberedheteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of the 5-10 membered heteroaryl is optionally substituted byoxo to form a carbonyl group; and wherein the C₆₋₁₀ aryl and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁰; R¹ is OR³ or NR⁴R⁵; R² isselected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, halo, CN, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2) S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²⁰; A¹ is selected from N and CR⁶; A² is selected from Nand CR⁷; A³ is selected from N and CR⁸; A⁴ is selected from N and CR⁹;R³ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-14 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and 5-10membered heteroaryl-C₁₋₃ alkylene; wherein said C₁₋₆ alkyl issubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(30A); and wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-14 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-14 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³⁰; R⁴ is selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-14 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-14 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, and 5-10 membered heteroaryl-C₁₋₃ alkylene;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-14 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-14 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁴⁰; R⁵ is selected from H and C₁₋₆ alkyl;wherein said C₁₋₆ alkyl is optionally substituted with 1 or 2substituents independently selected from R^(g); R⁶, R⁷, R⁸, and R⁹ areeach independently selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),NR^(c2)R^(a2) S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²⁰; each R¹⁰ is independentlyselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹; each R¹¹ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3) NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR³S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3) S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹²; each R¹² isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-7membered heterocycloalkyl, halo, D, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR⁵R^(d5) NR⁵C(O)R^(b5)NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R²⁰ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, halo, D, CN, OR^(a4), SR^(a4), C(O)R^(b4),C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(30A) is independentlyselected from C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), NR^(c6)R^(d6) NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6),NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6),S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6);wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R³¹; each R³⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),NR^(b6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R³¹; each R³¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN,OR^(a8), SR^(a8), C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8),NR^(c8)R^(d8), NR^(c8)C(O)R^(b8), NR^(c8)C(O)OR^(a8), NR^(c8)S(O)R^(b8),NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)₂R^(b8), and S(O)₂NR^(c8)R^(d8); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); each R⁴⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R⁴¹; each R⁴¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN,OR^(a9), SR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9),NR^(c9)R^(d9), NR^(c9)C(O)R^(b9), NR^(c9)C(O)OR^(a9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), and S(O)₂NR^(c9)R^(d9); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); each R^(a1), R^(c1) and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹¹; or any R^(c1) andR^(d1) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹; each R^(b1) is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹; each R^(e1) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl; each R^(a2), R^(c2), and R^(d2) is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R²⁰; or any R^(c2) andR^(d2) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R²⁰; each R^(b2) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²⁰; each R^(a3), R^(c3) and R^(d3) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²; or any R^(c3) andR^(d3) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R¹²; each R^(b3) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²; each R^(a4), R^(c4) and R^(d4) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); or any R^(c4) andR^(d4) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R^(g); each R^(b4) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(a5), R^(c5) and R^(d5) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyland C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); or any R^(c5) and R^(d5) attached tothe same N atom, together with the N atom to which they are attached,form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆alkenyl and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R^(a6), R^(c6)and R^(d6) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR³¹; or any R^(c6) and R^(d6) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R³¹; each R^(b6) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R³¹; each R^(a7), R^(c7)and R^(d7) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR⁴¹; or any R^(c7) and R^(d7) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R⁴¹; each R^(b7) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R⁴¹; each R^(a8), R^(c8)and R^(d8) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); each R^(b8) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(a9), R^(c9) and R^(d9) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyland C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(b9) is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); and each R^(g) is independently selected from OH, NO₂, CN, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,C₃₋₆ cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein A¹ is CR⁶.
 3. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein A² is CR⁷.
 4. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein A³ is CR⁸.
 5. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein A³ is N.
 6. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein A⁴ is CR⁹.
 7. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein A is CR⁶; A² is CR⁷; A³ is CR⁸; and A⁴is CR⁹.
 8. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein A is CR⁶; A² is CR⁷; A³ is N; and A⁴ is CR⁹. 9.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein A is CR⁶; A² is CR⁷; and A⁴ is CR⁹.
 10. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R⁶, R⁷, R⁸, andR⁹ are each independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), NR^(c2)R^(d2) S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); whereinsaid C₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4substituents independently selected from R²⁰.
 11. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R⁶, R⁷, R⁸,and R⁹ are each independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, 5-10 membered heteroaryl, halo, CN, OR^(a2), C(O)R^(b2),C(O)NR²R², C(O)OR^(a2), NR^(c2)R^(d2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R²⁰.
 12. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁶, R⁷, R⁸, and R⁹ are each independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), C(O)NR^(c2)R^(d2), andS(O)₂R^(b2).
 13. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁶, R⁷, R⁸, and R⁹ are eachindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-10 memberedheteroaryl, halo, CN, OR^(a2), C(O)NR^(c2)R^(d2), and S(O)₂R^(b2). 14.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁶ is H or C(O)NR^(c2)R^(d2).
 15. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁶ is H or C(O)NHCH₃.16. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁶ is H or 5-10 membered heteroaryl.
 17. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁷ isH.
 18. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁸ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2),or S(O)₂R^(b2).
 19. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is H, methyl, CHF₂, F, CN, OH, orS(O)₂(CH₃)₂.
 20. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁹ is H or halo.
 21. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁹ is Hor F.
 22. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is OR³.
 23. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is NR⁴R⁵.
 24. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl;wherein said C₁₋₆ alkyl is substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(30A) and wherein said 4-6 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R³.
 25. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R³ is 4-6 membered heterocycloalkyloptionally substituted with 1 or 2 substituents independently selectedfrom R³⁰.
 26. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R³ is tetrahydrofuran-3-yl optionally substitutedwith 1 or 2 substituents independently selected from R³⁰.
 27. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is tetrahydrofuran-3-yl.
 28. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁴ is selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-6 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R⁴⁰.
 29. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is4-6 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4substituents independently selected from R⁴⁰.
 30. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R⁴ istetrahydrofuran-3-yl.
 31. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is H.
 32. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R² is H.
 33. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Cy¹ is 5-6 membered heteroaryl optionally substituted with 1 or2 substituents independently selected from R¹⁰.
 34. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Cy¹ isphenyl optionally substituted with 1 or 2 substituents independentlyselected from R¹⁰.
 35. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Cy¹ is selected from phenyl and 5-6membered heteroaryl; wherein the phenyl and 5-6 membered heteroaryl areeach optionally substituted with 1 or 2 substituents independentlyselected from R¹⁰.
 36. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Cy¹ is phenyl, pyrazolyl or pyridinyl,each of which is optionally substituted with 1 or 2 substituentsindependently selected from R¹⁰.
 37. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Cy¹ is phenyl,pyrazolyl, triazolyl, oxazolyl, 2-oxo-1,2-dihydropyridinyl, pyridazinyl,or pyridinyl, each of which is optionally substituted with 1 or 2substituents independently selected from R¹⁰.
 38. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein Cy¹ ispyrazolyl optionally substituted with 1 or 2 substituents independentlyselected from R¹⁰.
 39. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R¹⁰ is independently selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, halo, D, CN, OR^(a1), and NR^(c1)R^(d1); wherein saidC₁₋₆ alkyl and 4-6 membered heterocycloalkyl are each optionallysubstituted with 1 or 2 substituents independently selected from R¹¹.40. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R¹⁰ is independently selected from methyl, ethyl,propyl, isopropyl, piperidinyl, piperazinyl, azetidinyl, morpholino,cyclopropyl, and cyclobutyl; each of which is optionally substitutedwith 1 or 2 substituents independently selected from R¹¹.
 41. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each R¹⁰ is independently selected from methyl, ethyl, propyl,isopropyl, piperidinyl, piperazinyl, azetidinyl, morpholino,cyclopropyl, ethylamino, and cyclobutyl; each of which is optionallysubstituted with 1 or 2 substituents independently selected from R¹¹.42. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R¹⁰ is independently selected from methyl,isopropyl, 2-hydroxypropan-2-yl, NH(CH₃), methylpiperidin-4-yl,methylpiperazin-1-yl, morpholinoethyl, 1-methylazetidin-3-yl,morpholino, cyclopropyl, and cyclobutyl.
 43. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein each R¹⁰ isindependently selected from methyl, ethyl, isopropyl,2-hydroxypropan-2-yl, NH(CH₃), methylpiperidin-4-yl,methylpiperazin-1-yl, morpholinoethyl, 1-methylazetidin-3-yl,morpholino, cyclopropyl, ethylamino, hydroxyethyl-2-yl, cyanoethyl-2-yl,dimethylamino-2-oxoethyl, 2-hydroxy-2-methylpropyl, 2-methoxyethyl,pyridin-3-ylmethyl, (tetrahydro-2H-pyran-4-yl)methyl, 2-morpholinoethyl,3-fluoro-1-methylpiperidin-4-yl,((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl,1-isopropylpiperidin-4-yl, 4-fluoro-1-methylpiperidin-4-yl,4-methylpiperazin-1-yl, tetrahydrofuran-3-yl,1,1-dioxidotetrahydrothiophen-3-yl, and cyclobutyl.
 44. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R¹⁰ ismethyl.
 45. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein each R¹¹ is independently selected from C₁₋₆alkyl, 4-6 membered heterocycloalkyl, and OR^(a3); wherein said C₁₋₆alkyl and 4-6 membered heterocycloalkyl are each optionally substitutedwith 1 or 2 substituents independently selected from R¹².
 46. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each R¹¹ is independently selected from C₁₋₆ alkyl, CN, 4-7membered heterocycloalkyl, C(O)NR^(c3)R^(d3), halo, 5-10 memberedheteroaryl, and OR^(a3); wherein said C₁₋₆ alkyl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1 or 2substituents independently selected from R¹².
 47. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein each R¹¹ isindependently selected from C₁₋₆ alkyl, 4-6 membered heterocycloalkyl,and OR^(a3).
 48. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R¹¹ is independently selected fromC₁₋₆ alkyl, CN, 4-7 membered heterocycloalkyl, C(O)NR^(c3)R^(d3), halo,and OR^(a3).
 49. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R¹¹ is independently selected frommethyl, OH, and morpholino.
 50. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R¹¹ isindependently selected from methyl, OH, methoxy, CN, C(O)N(CH₃)₂,isopropyl, pyridinyl, tetrahydropyranyl, fluoro,2-oxa-5-azabicyclo[2.2.1]heptanyl, and morpholino.
 51. The compound ofclaim 1, each R²⁰ is independently selected from D.
 52. The compound ofclaim 1, having Formula IIa:

or a pharmaceutically acceptable salt thereof.
 53. The compound of claim1, having Formula IIb:

or a pharmaceutically acceptable salt thereof.
 54. The compound of claim1, having Formula IIIa:

or a pharmaceutically acceptable salt thereof, wherein X is O or NH. 55.The compound of claim 1, having Formula IIIb:

or a pharmaceutically acceptable salt thereof, wherein X is O or NH. 56.The compound of claim 1, having Formula IVc:

or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.57. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein: Cy¹ is selected from C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein each 5-10 membered heteroaryl has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl is optionally substituted by oxo to form a carbonyl group;and wherein the C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰; R¹ is OR³ or NR⁴R⁵; R² is selected from H, D, andhalo; A¹ is selected from N and CR⁶; A² is selected from N and CR⁷; A³is selected from N and CR⁸; A⁴ is selected from N and CR⁹; R³ isselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-14membered heterocycloalkyl, wherein said C₃₋₁₀ cycloalkyl, and 4-14membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R³⁰; R⁴ is selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-14 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-14membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R⁴⁰; R⁵ is H; R⁶, R⁷, R⁸,and R⁹ is each independently selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, 5-10 membered heteroaryl, halo, CN, OR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²⁰; each R¹⁰ is independently selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, halo, D, CN, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), and S(O)₂R^(b1); whereinsaid C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl,are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹; each R¹¹ is independently selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, halo, D, CN, OR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3) andS(O)₂R^(b3); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, and 5-10 membered heteroaryl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²; each R¹² is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, CN, OR^(a5), and NR^(c5)R^(d5); each R²⁰ is independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, CN, OR^(a4), andNR^(c4)R^(d4); each R³⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl halo, D, CN, OR^(a6), and NR^(c6)R^(d6); each R⁴⁰ isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, CN,OR^(a7), and NR⁷R^(d7); each R^(a1), R^(c1) and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl; or any R^(c1) and R^(d1) attached to the sameN atom, together with the N atom to which they are attached, form a 4-,5-, or 6-membered heterocycloalkyl group optionally substituted with 1,2, 3, or 4 substituents independently selected from R¹¹; each R^(b1) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, and 4-10 membered heterocycloalkyl; each R^(a2), R^(c2), andR^(d2) is independently selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;wherein said C₁₋₆ alkyl, is optionally substituted with 1, 2, 3, or 4substituents independently selected from R²⁰; each R^(b2) isindependently selected from C₁₋₆ alkyl, and C₁₋₆ haloalkyl; each R^(a3),R^(c3) and R^(d3), is independently selected from H, C₁₋₆ alkyl, andC₁₋₆ haloalkyl; each R^(b3) is independently selected from C₁₋₆ alkyland C₁₋₆ haloalkyl; each R^(a4), R^(c4) and R^(d4), is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; each R^(a5), R^(c5) andR^(d5), is independently selected from H, C₁₋₆ alkyl, and C₁₋₆haloalkyl; each R^(a6), R^(c6) and R^(d6), is independently selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and each R^(a7), R^(c7) andR^(d7), is independently selected from H, C₁₋₆ alkyl, and C₁₋₆haloalkyl.
 58. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein: Cy¹ is selected from C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein each 5-10 membered heteroaryl has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl is optionally substituted by oxo to form a carbonyl group;and wherein the C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰; R¹ is OR³ or NR⁴R⁵; R² is H; A¹ is selected from Nand CR⁶; A² is selected from N and CR⁷; A³ is selected from N and CR⁸;A⁴ is selected from N and CR⁹; R³ is 4-14 membered heterocycloalkyl; R⁴is 4-14 membered heterocycloalkyl; R⁵ is H; R⁶, R⁷, R⁸, and R⁹ is eachindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-10 memberedheteroaryl, halo, CN, OR^(a2), C(O)NR^(c2)R^(d2), and S(O)₂R^(b2);wherein said C₁₋₆ alkyl and 5-10 membered heteroaryl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²⁰; each R¹⁰ is independently selected from C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, and NR^(c1)R^(d1); whereinsaid C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl,are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹; each R¹¹ is independently selected fromC₁₋₆ alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,halo, CN, OR^(a3), and C(O)NR^(c3)R^(d3); R²⁰ is D; each R^(c1) andR^(d1) is independently selected from H and C₁₋₆ alkyl; each R^(a2),R^(c2), and R^(d2) is independently selected from H and C₁₋₆ alkyl;wherein said C₁₋₆ alkyl, is optionally substituted with 1, 2, 3, or 4substituents independently selected from R²⁰; R^(b2) is C₁₋₆ alkyl; andeach R^(a3), R^(c3) and R^(d3), is independently selected from H andC₁₋₆ alkyl.
 59. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein: Cy¹ is selected from phenyl and 5-10membered heteroaryl; wherein each 5-10 membered heteroaryl has at leastone ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; and wherein the phenyl and 5-10membered heteroaryl are each optionally substituted with 1, 2 or 3substituents independently selected from R¹⁰; R¹ is OR³ or NR⁴R⁵; R² isH; A¹ is selected from N and CR⁶; A² is selected from N and CR⁷; A³ isselected from N and CR⁸; A⁴ is selected from N and CR⁹; R³ is 4-6membered heterocycloalkyl; R⁴ is 4-6 membered heterocycloalkyl; R⁵ is H;R⁶, R⁷, R⁸, and R⁹ is each independently selected from H, D, C₁₋₆ alkyl,C₁₋₆ haloalkyl, 5-6 membered heteroaryl, halo, CN, OR^(a2),C(O)NR^(c2)R^(d2), NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^(a1), andNR^(c1)R^(d1); wherein said C₁₋₆ alkyl and C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl, are each optionally substituted with 1 or 2substituents independently selected from R¹¹; each R¹¹ is independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR^(a3),C(O)NR^(c3)R^(d3), and NR^(c3)R^(d3); each R²⁰ is independently selectedfrom D; each R^(a1), R^(c1) and R^(d1) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl; each R^(a2), R^(c2), and R^(d2) isindependently selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; whereinsaid C₁₋₆ alkyl, is optionally substituted with 1, 2, or 3 substituentsindependently selected from R²⁰; each R^(b2) is independently selectedfrom C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and each R^(a3), R^(c3) and R^(d3),is independently selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl. 60.The compound of claim 1, wherein the compound is selected from:N-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;4-fluoro-N-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;4-fluoro-N,3-dimethyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-4-fluoro-N,3-dimethyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3-cyano-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)—N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;(S)-3-cyano-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-5-(6-(1-isopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide;(S)-5-(6-(1-isopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide;(S)-3,4-difluoro-N-methyl-5-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3,4-difluoro-N-methyl-5-(6-(4-(4-methylpiperazin-1-yl)phenyl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3,4-difluoro-N-methyl-5-(6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide(S)-3,4-difluoro-N-methyl-5-(6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide(S)-3,4-difluoro-N-methyl-5-(6-(6-methylpyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-4-fluoro-N,3-dimethyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3,4-difluoro-N-methyl-5-(6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)—N-methyl-5-(6-(4-(4-methylpiperazin-1-yl)phenyl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;(S)—N-methyl-5-(6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;(S)—N-methyl-5-(6-(6-morpholinopyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;(S)-5-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide;(S)-5-(6-(1-cyclobutyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide;(S)-3-(difluoromethyl)-4-fluoro-N-methyl-5-(6-(pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3-(difluoromethyl)-4-fluoro-N-methyl-5-(6-(5-methyl-6-(methylamino)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3-(difluoromethyl)-4-fluoro-5-(6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylbenzamide;(S)-3-(difluoromethyl)-4-fluoro-N-methyl-5-(6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3-cyano-N-methyl-5-(6-(pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3-cyano-N-methyl-5-(6-(6-methylpyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3-cyano-N-methyl-5-(6-(5-methylpyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3-cyano-N-methyl-5-(6-(pyridin-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-4-fluoro-3-hydroxy-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;and(S)-3-(6-(1-cyclobutyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methyl-5-(methylsulfonyl)benzamide;or a pharmaceutically acceptable salt of any of the aforementioned. 61.The compound of claim 1, wherein the compound is selected from:(S)-3-(1H-Indazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine;(S)-4-Fluoro-N,3-dimethyl-5-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-4-Fluoro-N,3-dimethyl-5-(6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-4-Fluoro-3-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,5-dimethylbenzamide;(S)-3-(6-(1-(2-Cyanoethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-N,5-dimethylbenzamide;3-(6-(1-(1,1-Dioxidotetrahydrothiophen-3-yl)-1H-pyrazol-4-yl)-5-(((S)-tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-N,5-dimethylbenzamide;(S)-3-(6-(1-(2-(Dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-N,5-dimethylbenzamide;(S)-4-Fluoro-3-(6-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,5-dimethylbenzamide;4-Fluoro-N,3-dimethyl-5-(6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-5-(((S)-tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-4-Fluoro-N,3-dimethyl-5-(6-(2-methyloxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3-(6-(1-Ethyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-N,5-dimethylbenzamide;(S)-4-Fluoro-N,3-dimethyl-5-(6-(pyridazin-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3-(5-(Ethylsulfonyl)-2,3-difluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-N-(tetrahydrofuran-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine;(S)-3-(5-(Ethylsulfonyl)-2,3-difluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine;(S)-3-(Difluoromethyl)-4-fluoro-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3-(Difluoromethyl)-5-(6-(1-ethyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-N-methylbenzamide;3-(Difluoromethyl)-4-fluoro-N-methyl-5-(6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-5-(((S)-tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3-(Difluoromethyl)-4-fluoro-5-(6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylbenzamide;(S)-3-(3-(1H-Pyrazol-3-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine;(S)-3,4-Difluoro-N-methyl-5-(6-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3-(6-(1-Ethyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4,5-difluoro-N-methylbenzamide;(S)-3,4-Difluoro-N-methyl-5-(6-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3,4-Difluoro-N-methyl-5-(6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)-3,4-Difluoro-5-(6-(1-isopropyl-2-oxo-1,2-dihydropyridin-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylbenzamide;(S)-3,4-Difluoro-5-(6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylbenzamide;(S)-3,4-Difluoro-N-methyl-5-(6-(2-methyloxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;(S)—N-Methyl-5-(6-(1-methyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;(S)—N-Methyl-5-(6-(2-methyl-2H-1,2,3-triazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;(S)—N-Ethyl-5-(6-(1-methyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;(S)—N-Isopropyl-5-(6-(1-methyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;(S)-5-(6-(1-Isopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(methyl-d₃)nicotinamide;4-Fluoro-3-(6-(1-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(((S)-tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-methyl-N-(methyl-d₃)benzamide;4-Fluoro-3-(6-(1-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(((S)-tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,5-dimethylbenzamide;3-(6-(6-(((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)pyridin-3-yl)-5-(((S)-tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-5-(difluoromethyl)-4-fluoro-N-(methyl-d₃)benzamide;(S)-4-Fluoro-3-(6-(2-(1-isopropylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-5-methyl-N-(methyl-d₃)benzamide;(S)-4-Fluoro-3-(6-(2-(1-isopropylpiperidin-4-yl)oxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-5-methyl-N-(methyl-d₃)benzamide;(S)-4-Fluoro-3-(6-(2-(4-fluoro-1-methylpiperidin-4-yl)oxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,5-dimethylbenzamide;and(S)-4-Fluoro-N,3-dimethyl-5-(6-(2-(4-methylpiperazin-1-yl)oxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;or a pharmaceutically acceptable salt of any of the aforementioned. 62.A pharmaceutical composition comprising a compound of claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.
 63. A method of inhibiting an FGFR3enzyme comprising contacting said enzyme with a compound of claim 1 or apharmaceutically acceptable salt thereof.
 64. A method of treatingcancer in a patient comprising administering to said patient atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 65. A method of treatingcancer in a patient comprising administering to said patient atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof in combination with anothertherapy or therapeutic agent.
 66. The method of claim 64, wherein saidcancer is selected from hepatocellular cancer, bladder cancer, breastcancer, cervical cancer, colorectal cancer, endometrial cancer, gastriccancer, head and neck cancer, kidney cancer, liver cancer,cholangiocarcinoma, lung cancer, ovarian cancer, prostate cancer,esophageal cancer, gall bladder cancer, pancreatic cancer, thyroidcancer, skin cancer, leukemia, multiple myeloma, chronic lymphocyticlymphoma, adult T cell leukemia, B-cell lymphoma, acute myelogenousleukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom'sMacroglubulinemia, hairy cell lymphoma, Burkett's lymphoma,glioblastoma, melanoma, and rhabdosarcoma.
 67. The method of claim 64,wherein said cancer is selected from bladder cancer, breast cancer,colorectal cancer, endometrial cancer, gastric cancer, head and neckcancer, kidney cancer, liver cancer, cholangiocarcinoma, lung cancer,ovarian cancer, pancreatic cancer, glioblastoma, melanoma, andrhabdosarcoma.
 68. A method for treating a skeletal or chondrocytedisorder in a patient comprising administering to said patient atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 69. The method of claim 68wherein said skeletal or chondrocyte disorder is selected fromachrondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia(TD), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome,Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, andcraniosynostosis syndrome.